New analogues of camptothecin, their use as medicaments and the pharmaceutical compositions containing them

ABSTRACT

A compound of the formula  
                 
 
     wherein the substituents are defined as in the specification which compounds are useful in the treatment of cancer.

[0001] Camptothecin is a natural compound which has been isolated forthe first time from the leaves and the bark of the Chinese plant calledcamptotheca acuminata (see Wall et al. J. Amer. Chem. Soc. 88:3888(1966)). Camptothecin is a pentacyclic compound constituted by anindolizino[1,2-b]quinoline fragment fused with an α-hydroxylactone withsix members. The carbon in position 20 which carries the α-hydroxy groupis asymmetrical and confers a rotatory power on the molecule. Thenatural form of camptothecin has an absolute “S” configuration asregards the carbon 20 and corresponds to the following formula:

[0002] Camptothecin has an anti-proliferative activity in severalcancerous cell lines, including the cell lines of human tumors of thecolon, lung and breast (Suffness, M et al: The Alkaloids Chemistry andPharmacology, Bross A., ed., Vol. 25, p. 73 (Acedemic Press, 1985)). Itis suggested that the anti-proliferative activity of camptothecin isrelated to its inhibitory activity on DNA topoisomerase I.

[0003] It has been indicated that α-hydroxylactone was an absoluterequirement both for the in vivo and in vitro activity of campotothecin(Camptothecins: New Anticancer Agents, Putmesil, M et al, ed., p. 27(CRC Press, 1995); Wall M. et al, Cancer Res. 55:753 (1995); Hertzberget al, J. Med. Chem. 32:715 (1982) and Crow et al, J. Med. Chem. 35:4160(1992)). The present invention relates to a new class of compounds ofcamptothecin, in which a β-hydroxylactone replaces the naturalα-hydroxylactone of camptothecin. The compounds according to the presentinvention present a powerful biological activity which is unexpectedwith regard to the state of the prior art.

[0004] Therefore a subject of the invention is new analogues ofcamptothecin which differ from all known derivatives of camptothecin inthe sense that they contain β-hydroxylactone (or its openhydroxycarboxylic form) instead of an α-hydroxylactone (or its openhydroxycarboxylic form); or a pharmaceutically acceptable salt of one ofthe latter. By derivative of camptothecin is meant a compound having thesame structural skeleton as that of camptothecin (i.e. anindolizino[1,2-b]quinoline fragment fused with an α-hydroxylactone withsix members), with or without other chemical substitutions on theskeletal structure. Different derivatives of camptothecin are well knownby specialists, as described hereafter. By β-hydroxylactone is meant alactone which contains an additional carbon atom between the carbon ofthe carboxyl and the α-carbon carrying the hydroxyl group in theα-hydroxylactone.

[0005] An analogue of camptothecin according to the invention cantherefore contain substitutions on the indolizino[1,2-b]quinolinefragment (for example in order to improve the solubility of thecompound), or on the open or closed β-hydroxylactone (for example inorder to improve the stability of the compound). Examples ofsubstitutions on the closed β-hydroxylactone include an alkylsubstitution (for example ethyl) on the β-carbon. Examples ofsubstitutions on the open β-hydroxylactone include alkyl substitutionson the β-carbon, substitutions (for example an amidation) on theresultant carboxylic acid and substitutions (for example anesterification) or suppressions of the resultant hydroxyl group.

[0006] Preferred β-hydroxylactone camptothecin analogues are notablythose in which the pentacyclic skeletton is substituted at least once byan halogen atom in any of positions 8, 9, 10, 11 or 12.

[0007] The invention first relates to compounds of general formula (A₁)or (A₂)

[0008] in racemic or enantiomeric form or any combinations of theseforms, in which

[0009] Z₁ represents a lower alkyl, a lower alkenyl, a lower alkynyl, alower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio loweralkyl;

[0010] Z₂, Z₃, Z₄, Z₅ and Z₆ represent, independently,

[0011] i) H, halo, lower haloalkyl, alkyl containing 1 to 12 carbonatoms optionnally substituted by one or more halo radicals indentical ordifferent, lower alkenyl, cycloalkyl, cycloalkyl lower alkyl, cyano,lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl,hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, lower alkyllower sulphonylalkyl, —(CH₂)_(m)NZ′₆Z′₇, —(CH₂)_(m)OZ′₆, —(CH₂)_(m)SZ′₆,—(CH₂)_(m)CO₂Z′₆, —(CH₂)_(m)NZ′₆C(O)Z₈—(CH₂)_(m)C(O)Z₈,—(CH₂)_(m)OC(O)Z₈, —O(CH₂)_(m)NZ′₆Z′₇, —OC(O)NZ′₆Z′₇,—OC(O)(CH₂)_(m)CO₂Z′₆, —OSO₂Z₇, —(CH₂)_(m)N(CH₃)(CH₂)_(n)NZ′₆Z′₇,—(CH₂)_(m)OC(O)NZ′₆Z′₇, —(CH₂)_(m)S(O)_(q)Z₁₁, —C(CH₂)_(m)P(O)Z₁₂Z₁₃,—(CH₂)₂P(S)Z₁₂Z₁₃, —(CH₂)_(m)SiZ′₁₁Z′₁₂Z₁₃; or ii) —(CH₂)_(n)[N═X],—OC(O)[N═X], —(CH₂)_(m)OC(O)[N═X], aryl or lower arylalkyl, eachsubstituted (i.e. substituted between once and four times on the arylgroup or the heterocycle) or non substituted in which the substituent isa lower alkyl, lower arylalkyl, halo, hydroxy, —OCF₃, nitro, amino,lower alkylamino, di(lower alkyl)amino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl or iii) Z₃ and Z₄or Z₄ and Z₅ form together a chain with 3 or 4 members in which theelements of the chain are selected from the group constituted by CH,CH₂, O, S, N or NZ₉;

[0012] Z₇ represents a lower alkyl radical optionnally substituted byone or more halo radicals identical or different, or an aryl optionnallysusbtituted by one or more lower alkyl radicals identical or different;

[0013] Z′₆ and Z′₇ represent, independently, i) H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or ii) aryl or lower arylalkyl, each substituted(i.e. substituted between once and four times on the aryl group) or nonsubstituted in which the substituent is a lower alkyl, halo, nitro,amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, loweralkoxy or lower alkoxy lower alkyl;

[0014] Z₈ represents i) H, a lower alkyl, lower hydroxyalkyl, amino,lower alkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, loweralkoxy lower alkyl, lower haloalkyl, or ii) aryl or lower arylalkyl,each substituted (i.e. substituted between once and four times on thearyl group) or non substituted, in which the substituent is a loweralkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

[0015] Z₉ represents i) H, a lower alkyl, lower haloalkyl, or ii) arylor lower arylalkyl, each substituted or non substitutued in which thesubstituent is lower alkyl, halo, nitro, amino, lower alkylamino, lowerhaloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

[0016] Z₁₀ represents i) H, a lower alkyl, lower haloalkyl, loweralkoxy, or ii) aryl substituted (i.e. having one to four substituents onthe aryl group)or non substituted in which the substitutent is loweralkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;

[0017] Z₁₁ represents a lower alkyl, aryl, —(CH₂)_(m)OZ₁₄,—(CH₂)_(m)SZ₁₄, —(CH₂)₂NZ₁₄Z₁₅ or —(CH₂)_(m)[N═X];

[0018] Z₁₂ and Z₁₃ represent, independently, a lower alkyl, aryl, loweralkoxy, aryloxy or amino;

[0019] Z′₁₁, Z′₁₂ and Z′₁₃ represent, independently, H or a lower alkylradical;

[0020] Z₁₄ and Z₁₅ represent, independently, H, lower alkyl or aryl;

[0021] Z₁₆ represents H or —OZ₂₁;

[0022] Z₁₇ represents —OZ′₆ or —NZ′₆Z′₇;

[0023] Z₁₈ and Z₁₉ represent, independently, H, halo, lower alkyl, loweralkoxy or hydroxy;

[0024] Z₂₀ represents H or halo;

[0025] Z₂₁ represents H, a lower alkyl, —CHO or —C(O)(CH₂)_(m)CH₃;

[0026] Z_(p) represents H or an easily cleavable group preferably chosenfrom the groups corresponding to the formula —C(O)—A—NZ₂₂Z₂₃, in which Arepresents a linear or branched alkylene radical optionally substitutedby a radical chosen from the free, esterified or salified hydroxy,halogen, free, esterified or salified carboxy, amino, mono ordialkylamino radicals;

[0027] Z₂₂ and Z₂₃ represent, independently, H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e., substituted one to four times on the aryl group), inwhich the substituent is a lower alkyl, halo, nitro, amino, loweralkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or loweralkoxy lower alkyl;

[0028] m is an integer comprised between 0 and 6;

[0029] n is 1 or 2; and

[0030] q represents an integer from 0 to 2; and

[0031] [N═X] represents a heterocyclic group with 4 to 7 members withthe nitrogen atom which is a member of the heterocyclic ring, and Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S, CH₂, CH, N, NZ₉ andC(O)Z₁₀;

[0032] or pharmaceutically acceptable salts thereof.

[0033] The invention preferably relates to compounds of general formula(A₁) or (A₂) as defined above, in racemic or enantiomeric form or anycombinations of these forms, characterized in that

[0034] Z₁ represents a lower alkyl, a lower alkenyl, a lower alkynyl, alower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio loweralkyl;

[0035] Z₂ represents H, halo or —OSO₂Z₇;

[0036] Z₃, Z₄ and Z₅ represent, independently, i) H, halo, lowerhaloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro,lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lowerhydrazinoalkyl, azido, lower azidoalkyl, —(CH₂)_(m)NZ′₆Z₇,—(CH₂)_(m)OZ′₆, —(CH₂)_(m)SZ′₆, —(CH₂)_(m)CO₂Z′₆, —(CH₂)_(m)NZ′₆C(O)Z₈,—(CH₂)_(m)C(O)Z₈, —(CH₂)_(m)OC(O)Z₈, —O(CH₂)_(m)NZ′₆Z′₇, —OC(O)NZ′₆Z′₇,OC(O)(CH₂)_(m)CO₂Z′₆, —OSO₂Z₇ or ii) —(CH₂)_(n)[N═X], —OC(O)[N═X],—(CH₂)_(m)OC(O)[N═X] (in which [N═X], in this invention, represents aheterocyclic group with 4 to 7 members with the nitrogen atom N, whichis a member of the heterocyclic group, and X represents the remainingmembers, which are necessary to complete the heterocylic group, selectedfrom the group constituted by O, S, CH₂, CH, N, NZ₉ and COZ₁₀), aryl orlower arylalkyl, each substituted (i.e. substituted between once andfour times on the aryl group or the heterocycle) or non substituted inwhich the substituent is a lower alkyl, halo, nitro, amino, loweralkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or loweralkoxy lower alkyl or iii) Z₃ and Z₄ or Z₄ and Z₅ form together a chainwith 3 or 4 members in which the elements of the chain are selected fromthe group constituted by CH, CH₂, O, S, N or NZ₉;

[0037] Z₆ represents i) H, halo, lower haloalkyl, alkyl containing 1 to12 carbon atoms optionnally substituted by one or more halo radicalsindentical or different, lower alkoxy, lower alkoxy lower alkyl, loweralkylthio lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyano,cyanoalkyl, lower alkyl lower sulphonylalkyl, lower hydroxyalkyl, nitro,—(CH₂)_(m)C(O)Z₈, —(CH₂)_(m)NZ′₆C(O)Z₈, —(CH₂)_(m)NZ′₆Z′₇,—CH₂)_(m)N(CH₃)(CH₂)_(n)NZ′₆Z′₇, —CH₂)_(m)OC(O)Z₈,—(CH₂)_(m)OC(O)NZ′₆Z′₇, —(CH₂)_(m)S(O)_(q)Z₁₁, —(CH₂)_(m)P(O)Z₁₂Z₁₃,—(CH₂)₂P(S)Z₁₂Z₁₃, —(CH₂)_(m)SiZ′₁₁Z′₁₂Z′₁₃; or ii) —(CH₂)_(n)[N═X],—OC(O)[N═X], —(CH₂)_(m)OC(O)[N═X], each substituted (i.e. substitutedbetween once and four times on the heteroaryl group) or non substitutedin which the substituent is a lower alkyl, lower arylalkyl, halo,hydroxy, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl; or iii) aryl orlower arylalkyl, each substituted (i.e. substituted between once andfour times on the aryl group) or non substituted in which thesubstituent is a lower alkyl, halo, hydroxy, nitro, —OCF₃, amino, loweralkylamino, di(lower alkyl)amino, lower haloalkyl, lower hydroxyalkyl,lower alkoxy or lower alkoxy lower alkyl;

[0038] Z₇ represents a lower alkyl radical optionnally substituted byone or more halo radicals identical or different, or an aryl optionnallysusbtituted by one or more lower alkyl radicals identical or different;

[0039] Z′₆ and Z′₇ represent, independently, i) H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or ii) aryl or lower arylalkyl, each substituted(i.e. substituted between once and four times on the aryl group) or nonsubstituted in which the substituent is a lower alkyl, halo, nitro,amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, loweralkoxy or lower alkoxy lower alkyl;

[0040] Z₈ represents i) H, a lower alkyl, lower hydroxyalkyl, amino,lower alkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, loweralkoxy lower alkyl, lower haloalkyl, or ii) aryl or lower arylalkyl,each substituted (i.e. substituted between once and four times on thearyl group) or non substituted, in which the substituent is a loweralkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

[0041] Z₉ represents i) H, a lower alkyl, lower haloalkyl, or ii) arylor lower arylalkyl, each substituted or non substitutued in which thesubstituent is lower alkyl, halo, nitro, amino, lower alkylamino, lowerhaloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

[0042] Z₁₀ represents i) H, a lower alkyl, lower haloalkyl, loweralkoxy, or ii) aryl substituted (i.e. having one to four substituents onthe aryl group)or non substituted in which the substitutent is loweralkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;

[0043] Z₁₁ represents a lower alkyl, aryl, —(CH₂)_(m)OZ₁₄,—(CH₂)_(m)SZ₁₄, —(CH₂)₂NZ₁₄Z₁₅ or —(CH₂)_(m)[N═X];

[0044] Z₁₂ and Z₁₃ represent, independently, a lower alkyl, aryl, loweralkoxy, aryloxy or amino;

[0045] Z′₁₁, Z′₁₂ and Z′₁₃ represent, independently, H or a lower alkylradical;

[0046] Z₁₄ and Z₁₅ represent, independently, H, lower alkyl or aryl;

[0047] Z₁₆ represents H or —OZ₂₁;

[0048] Z₁₇ represents —OZ′₆ or —NZ′₆Z′₇;

[0049] Z₁₈ and Z₁₉ represent, independently, H, halo, lower alkyl, loweralkoxy or hydroxy;

[0050] Z₂₀ represents H or halo;

[0051] Z₂₁ represents H, a lower alkyl, —CHO or —C(O)(CH₂ _(m)CH₃;

[0052] Z_(p) represents H or an easily cleavable group preferably chosenfrom the groups corresponding to the formula —C(O)—A—NZ₂₂Z₂₃, in which Arepresents a linear or branched alkylene radical optionally substitutedby a radical chosen from the free, esterified or salified hydroxy,halogen, free, esterified or salified carboxy, amino, mono ordialkylamino radicals;

[0053] Z₂₂ and Z₂₃ represent, independently, H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e., substituted one to four times on the aryl group), inwhich the substituent is a lower alkyl, halo, nitro, amino, loweralkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or loweralkoxy lower alkyl

[0054] m is an integer comprised between 0 and 6;

[0055] n is 1 or 2; and

[0056] q represents an integer from 0 to 2; and

[0057] [N═X] represents a heterocyclic group with 4 to 7 members withthe nitrogen atom which is a member of the heterocyclic ring, and Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S, CH₂, CH, N, NZ₉ and COZ₁₀;

[0058] or pharmaceutically acceptable salts thereof.

[0059] The invention more preferably relates to compounds of generalformula (A₁) or (A₂) as defined above, characterized in that Z₂represents H or halo; or pharmaceutically acceptable salts thereof.

[0060] The invention more preferably relates to compounds of generalformula (A₁) or (A₂) as defined above, characterized in that Z₃represents halo; or pharmaceutically acceptable salts thereof.

[0061] The invention more preferably relates also to compounds ofgeneral formula (A₁) or (A₂) as defined above, characterized in that

[0062] Z₁ represents a lower alkyl;

[0063] Z₂ represents H or halo;

[0064] Z₃, Z₄ and Z₅ represent, independently, i) H, halo, lower alkyl,—(CH₂)_(m)NZ′₆Z′₇, —(CH₂)_(m)OZ′₆, —OSO₂Z₇ or ii) —(CH₂)_(n)[N═X] oriii) Z₃ and Z₄ or Z₄ and Z₅ form together a chain with 3 or 4 members inwhich the elements of the chain are selected from the group constitutedby CH, CH₂, O, S, N or NZ₉;

[0065] Z₆ represents i) H, halo, alkyl containing 1 to 12 carbon atomsoptionnally substituted by one or more halo radicals indentical ordifferent, lower alkoxy lower alkyl, cycloalkyl, cycloalkyl lower alkyl,lower hydroxyalkyl, —(CH₂)_(m)NZ′₆Z′₇, —(CH₂)mSiZ′₁₁Z′₁₂Z′₁₃; or ii)—(CH₂)_(n)[N═X] substituted or non substituted in which the substituentis a lower alkyl or lower arylalkyl or iii) aryl or lower arylalkyl,each substituted or non substituted in which the substituent is a loweralkyl, halo, —OCF₃, di(lower alkyl)amino or lower haloalkyl;

[0066] Z₇ represents a lower alkyl radical optionnally substituted byone or more halo radicals identical or different;

[0067] Z′₆ and Z′₇ represent, independently, i) H, a lower alkyl, or ii)lower arylalkyl;

[0068] Z₉ represents a lower alkyl or lower arylalkyl;

[0069] Z′₁₁, Z′₁₂ and Z′₁₃ represent, independently, a lower alkylradical;

[0070] Z₁₆ represents H or —OZ₂₁;

[0071] Z₁₇ represents —OZ′₆ or —NZ′₆Z′₇;

[0072] Z₁₈ and Z₁₉ represent, independently, H, halo;

[0073] Z₂₀ represents H;

[0074] Z₂₁ represents H, a lower alkyl or —C(O)(CH₂)_(m)CH₃;

[0075] Z_(p) represents H or a group corresponding to the formula—C(O)—A—NZ₂₂Z₂₃, in which A represents a linear or branched alkyleneradical optionally substituted by a radical chosen from the free,esterified or salified hydroxy, halogen, free, esterified or salifiedcarboxy, amino, mono or dialkylamino radicals;

[0076] Z₂₂ and Z₂₃ represent, independently, H, a lower alkyl;

[0077] m is an integer comprised between 0 and 6;

[0078] n is 1 or 2; and

[0079] q represents an integer from 0 to 2; and

[0080] [N═X] represents a heterocyclic group with 4 to 7 members, Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, CH₂, CH, N and NZ₉;

[0081] or pharmaceutically acceptable salts thereof.

[0082] The invention more preferably relates also to compounds ofgeneral formula (A₁) or (A₂) as defined above, characterized in thatZ₁₈, Z₁₉ and Z₂₀ represent H; or pharmaceutically acceptable saltsthereof.

[0083] The invention more preferably relates also to compounds ofgeneral formula (A₁) or (A₂) as defined above, characterized in that Z₁represents ethyl; or pharmaceutically acceptable salts thereof.

[0084] The invention preferably relates also to compounds of generalformula (A₁) or (A₂) as defined above, characterized in that Z_(p)represents a group corresponding to the formula —C(O)—A—NZ₂₂Z₂₃; orpharmaceutically acceptable salts thereof.

[0085] The invention preferably relates also to compounds of generalformula (A₁) or (A₂) as defined above, characterized in that Z_(p)represents H; or pharmaceutically acceptable salts thereof.

[0086] The invention preferably relates also to compounds as definedabove, characterized in that they correspond to the formula (A₁)

[0087] wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₁₈, Z₁₉, Z₂₀ and Z_(p) are asdefined above; or pharmaceutically acceptable salts thereof.

[0088] The invention preferably relates also to compounds as definedabove, characterized in that they correspond to the formula (A2)

[0089] wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₁₆, Z₁₇, Z₁₈, Z₁₉, Z₂₀ and Z_(p)are as defined above; or pharmaceutically acceptable salts thereof.

[0090] The invention preferably relates also to compounds as definedabove, characterized in that Z₆ represents —(CH₂)_(m)SiZ′₁₁Z′₁₂Z′₁₃; orpharmaceutically acceptable salts thereof.

[0091] The invention preferably relates also to compounds as definedabove, characterized in that they correspond to the following formula:

[0092](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2-trimethylsilylethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-done;

[0093](5R)-5-ethyl-5-hydroxy-12-(2-trimethylsilylethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione.

[0094] More preferably, the invention relates also to compounds asdefined above, characterized in that Z₂ represents H or halo, Z₃represents halo, Z₄ represents H, halo or lower alkyl, Z₅ represents Hor halo, and Z₆ represents H, lower alkyl or —(CH₂)_(n)[N═X] substitutedin which the substituent is a lower alkyl; or pharmaceuticallyacceptable salts thereof.

[0095] More preferably, the invention relates also to compounds asdefined above, characterized in that they correspond to the followingformula:

[0096](5R)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0097] (5R)-5-ethyl-9,11 -difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;or pharmaceutically acceptable salts thereof.

[0098] The invention relates also to compounds as defined above,characterized in that they correspond to the formula

[0099] wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₁₈, Z₁₉, Z₂₀ and Z_(p) are asdefined above; or pharmaceutically acceptable salts of thereof.

[0100] The invention relates to compounds of general formula (B1) and(B2)

[0101] in racemic or enantiomeric form or any combinations of theseforms, in which

[0102] R₁ represents a lower alkyl, a lower alkenyl, a lower alkynyl, alower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio loweralkyl;

[0103] R₂, R₃ and R₄represent, independently, H, halo, lower haloalkyl,lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lowernitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl,azido, lower azidoalkyl, (CH₂)_(m)NR₆R₇, (CH₂)_(m)OR₆, (CH₂)_(m)SR₆,(CH₂)_(m)CO₂R₆, (CH₂)_(m)NR₆C(O)R₈, (CH₂)_(m)C(O)R₈, (CH₂)_(m)OC(O)R₈,O(CH₂)_(m)NR₆R₇, OC(O)NR₆R₇, OC(O)(CH₂)_(m)CO₂R₆ or (CH₂)_(n)[N═X],OC(O)[N═X], (CH₂)_(m)OC(O)[N═X] (in which [N═X], in this invention,represents a heterocyclic group with 4 to 7 members with the nitrogenatom N, which is a member of the heterocyclic group, and X representsthe remaining members, which are necessary to complete the heterocylicgroup, selected from the group constituted by O, S, CH₂, CH, N, NR₉ andCOR₁₀), substituted or non substituted aryl or lower arylalkyl (i.e.substituted between once and four times on the aryl group or theheterocycle), in which the substituent is a lower alkyl, halo, nitro,amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, loweralkoxy or lower alkoxy lower alkyl) or R₂ and R₃ form together a chainwith 3 or 4 members in which the elements of the chain are selected fromthe group constituted by CH, CH₂, O, S, N or NR₉;

[0104] R₅ represents H, halo, lower haloalkyl, lower alkyl, loweralkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl,cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower alkyl lowersulphonylalkyl, lower hydroxyalkyl, nitro, (CH₂)_(m)C(O)R₈,(CH₂)_(m)NR₆C(O)R₈, (CH₂)_(m)NR₆R₇, (CH₂)_(m)N(CH₃)(CH₂)_(n)NR₆R₇,(CH₂)_(m)OC(O)₈, (CH₂)_(m)OC(O)NR₆R₇, (CH₂)_(m)S(O)_(q)R₁₁,(CH₂)_(m)P(O)R₁₂R₁₃, (CH₂)₂P(S)R₁₂R₁₃ or (CH₂)_(n)[N═X], OC(O)[N═X],(CH₂)_(m)OC(O)[N═X], substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the aryl orheteroaryl group), in which the substituent is a lower alkyl, halo,hydroxy, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

[0105] R₆ and R₇ represent, independently, H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

[0106] R₈ represents H, a lower alkyl, lower hydroxyalkyl, amino, loweralkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl,cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

[0107] R₉ represents H, a lower alkyl, lower haloalkyl, aryl, lowerarylalkyl, or aryl or lower arylalkyl in which the aryl group issubstituted by one or more groups chosen from the following radicals:lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl,lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

[0108] R₁₀ represents H, a lower alkyl, lower haloalkyl, lower alkoxy,aryl or aryl substituted (i.e. having one to four substituents on thearyl group) by one or more groups chosen from the following radicals:lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy loweralkyl;

[0109] R₁₁ represents a lower alkyl, aryl, (CH₂)_(m)OR₁₄, (CH₂)_(m)SR₁₄,(CH₂)₂NR₁₄R₁₅ or (CH₂)_(m)[N═X];

[0110] R₁₂ and R₁₃ represent, independently, a lower alkyl, aryl, loweralkoxy, aryloxy or amino;

[0111] R₁₄ and R₁₅ represent, independently, H, lower alkyl or aryl;

[0112] R₁₆ represents H or OR₂₁;

[0113] R₁₇ represents OR₆ or NR₆R₇;

[0114] R₁₈ and R₁₉ represent, independently, H, halo, lower alkyl, loweralkoxy or hydroxy; p1 R₂₀ represents H or halo;

[0115] R₂₁ represents H, a lower alkyl, CHO or C(O)(CH₂)_(m)CH₃;

[0116] R_(p) represents H or an easily cleavable group preferably chosenfrom the groups corresponding to the formula —C(O)—A—NR₂₂R₂₃, in which Arepresents a linear or branched alkylene radical optionally substitutedby a radical chosen from the free, esterified or salified hydroxy,halogen, free, esterified or salified carboxy, amino, mono ordialkylamino radicals, while R₂₂ and R₂₃, independently, represent H, alower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, loweraminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, loweralkoxy lower alkyl, lower haloalkyl, or substituted or non substitutedaryl or lower arylalkyl (i.e., substituted one to four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

[0117] m is an integer comprised between 0 and 6;

[0118] n is 1 or 2; and

[0119] q represents an integer from 0 to 2; and

[0120] [N═X] represents a heterocyclic group with 4 to 7 members, Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀;

[0121] or pharmaceutically acceptable salts thereof.

[0122] The invention especially relates to the compounds of generalformula (I_(A)) characterized in that they correspond either to formulaI′_(A)

[0123] in which

[0124] R₃₁ represents a lower alkyl radical;

[0125] R_(32,) R_(33,) R₃₄ and R₃₅ represent, independently, H, halo or—OSO₂R₄₀;

[0126] R₃₆ represents H, a linear or branched alkyl radical containing 1to 12 carbon atoms optionnally substituted by one or more halo radicalsindentical or different, lower hydroxy alkyl, lower alkoxy lower alkyl,a cycloalkyl, lower cycloalkyl alkyl, nitro, halo, —(CH₂)_(m)SiR₃₇R₃₈R₃₉radical, or an aryl substituted or non substituted or lower aryl alkylradical substituted or non substituted on the aryl group, thesubstituents of the aryl groups being identical or different andselected from: lower alkyl, hydroxy, halo, amino, lower alkyl amino,di(lower alkyl)amino, CF₃ or OCF₃;

[0127] R_(37,) R₃₈ and R₃₉ represent, independently, H or a lower alkylradical;

[0128] R₄₀ represents a lower alkyl radical optionnally substituted byone or more halo radicals identical or different, or an aryl optionnallysusbtituted by one or more lower alkyl radicals identical or different;

[0129] m is an integer comprised between 0 and 6;

[0130] it being understood that when R₃₂ represents H

[0131] R₃₆ represents a linear or branched alkyl radical containing 7 á12 carbon atoms, 13 (CH₂)_(m)SiR₃₇R₃₈R₃₉ or an aryle group substitutedby one or more substituents indentical or different and selected fromdi(lower alkyl)amino and OCF₃, and/or

[0132] at least one of the radicals R_(3,) R₄ and R₅ represents—OSO₂R₄₀;

[0133] or one of the following formulae:

[0134](5R)-5-ethyl-11-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0135](5R)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0136](5R)-12-benzyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0137](5R)-12-butyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0138](5R)-5,12-diethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0139](5R)-5-ethyl-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0140](5R)-12-cyclohexyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0141](5R)-5-ethyl-5-hydroxy-12-(4-methylphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0142](5R)-10-chloro-5-ethyl-12-(2-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-]quinoleine-3,15-dione;

[0143](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0144](5R)-5-ethyl-9-fluoro-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0145](5R)-12-butyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0146](5R)-12-benzyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0147](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0148](5R)-5,12-diethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0149](5R)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0150](5R)-12-butyl-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0151] (5R)-5,12-diethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0152](5R)-5-ethyl-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0153](5R)-12-butyl-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0154](5R)-5,12-diethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0155](5R)-5-Ethyl-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0156](5R)-5-ethyl-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0157](5R)-12-(2,6-difluorophenyl)-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0158](5R)-12-(3,5-difluorophenyl)-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0159](5R)-5-ethyl-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0160](5R)-5-ethyl-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0161](5R)-5-ethyl-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0162](5R)-5-ethyl-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0163](5R)-5-ethyl-9-fluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0164](5R)-12-(2,6-difluorophenyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0165](5R)-12-(3,5-difluorophenyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0166](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0167](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0168](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0169](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0170] (5R)-5-ethyl-9,10-difluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0171](5R)-12-(2,6-difluorophenyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0172](5R)-12-(3,5-difluorophenyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0173](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0174](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0175](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0176](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0177] (5R)-5-ethyl-9, 11-difluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0178](5R)-12-(2,6-difluorophenyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0179](5R)-12-(3,5-difluorophenyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0180](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0181] (5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0182](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0183] (5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0184](5R)-5-ethyl-9-fluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0185] (5R)-5-ethyl-9-fluoro-5-hydroxy-12-(3,3,3-trifluoropropyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0186] (5R)-5-ethyl-9-fluoro-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0187](5R)-5-ethyl-9-fluoro-5-hydroxy-12-pentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0188](5R)-5-ethyl-9-fluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0189] (5R)-12-(2-cyclohexylethyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0190](5R)-12-(3,3-dimethylbutyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0191](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0192](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(3,3,3-trifluoropropyl)-4,5,13,15tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0193](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0194](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-pentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0195](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0196](5R)-12-(2-cyclohexylethyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0197](5R)-12-(3,3-dimethylbutyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0198](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0199](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(3,3,3-trifluoropropyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0200](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0201](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-pentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0202](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0203] (5R)-12-(2-cyclohexylethyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0204](5R)-12-(3,3-dimethylbutyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0205](5R)-12-chloro-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0206](5R)-5-ethyl-5-hydroxy-12-hydroxymethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0207](5R)-5-ethyl-9-fluoro-5-hydroxy-12-isobutyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0208](5R)-5-ethyl-9-fluoro-5-hydroxy-12-neopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0209](5R)-5-ethyl-9-fluoro-12-(3-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0210](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(4-trifluoromethylphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0211](5R)-12-[4-(tert-butyl)phenyl]-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0212](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0213] (5R)-12-(2-ethoxyethyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0214](5R)-5-ethyl-9,10,11-trifluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione.;

[0215] or the salts thereof.

[0216] Preferred compounds of the invention of formula I_(A) are thosefor which R₃₁ represents an ethyl radical, as well as those for whichR₃₃ represents halo and in particular fluoro. Preferred compounds of theinvention of formula I′_(A) are those for which R₃₆ represents—(CH₂)_(m)SiR₃₇R₃₈R₃₉.

[0217] The preferred compounds of formula I correspond to the followingformulae:

[0218](5R)-5-ethyl-8-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0219] (5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2-trimethylsilylethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0220](5R)-5-ethyl-5-hydroxy-12-(2-trimethylsilylethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0221](5R)-12-decyl-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0222](5R)-12-decyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0223](5R)-12-decyl-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0224](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(4-trifluoromethoxyphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0225](5R)-12-(4-dimethylaminophenyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0226](5R)-5-ethyl-9-fluoro-5-hydroxy-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolein-10-yltrifluorometanesulfonate,

[0227] (5R)-5-ethyl-11-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0228](5R)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0229](5R)-12-benzyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0230] (5R)-12-butyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0231](5R)-5,12-diethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0232] (5R) -5-ethyl-5- hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0233](5R)-12-cyclohexyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0234](5R)-5-ethyl-5-hydroxy-12-(4-methylphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0235](5R)-10-chloro-5-ethyl-12-(2-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0236](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0237](5R)-5-ethyl-9-fluoro-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0238](5R)-12-butyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0239](5R)-12-benzyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0240](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0241](5R)-5,12-diethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0242](5R)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0243](5R)-12-butyl-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0244] (5R)-5,12-diethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0245](5R)-5-ethyl-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0246](5R)-12-butyl-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0247](5R)-5,12-diethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0248](5R)-5-Ethyl-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0249](5R)-5-ethyl-9-fluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0250](5R)-12-(3,5-difluorophenyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0251](5R)-5-ethyl-9-fluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0252](5R)-12-chloro-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0253](5R)-5-ethyl-5-hydroxy-12-hydroxymethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0254](5R)-5-ethyl-9-fluoro-5-hydroxy-12-isobutyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0255] (5R)-5-ethyl-9-fluoro-5-hydroxy-12-neopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0256](5R)-5-ethyl-9-fluoro-12-(3-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0257](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(4-trifluoromethylphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0258](5R)-12-[4-(tert-butyl)phenyl]-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0259](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0260](5R)-12-(2-ethoxyethyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0261](5R)-5-ethyl-9,10,11-trifluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3, 15-dione;

[0262] or the salts of the latter, and more particularly to thefollowing formulae:

[0263](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2-trimethylsilylethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0264](5R)-5-ethyl-5-hydroxy-12-(2-trimethylsilylethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0265](5R)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0266](5R)-5,12-diethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0267](5R)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0268] (5R)-5,12-diethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0269](5R)-5-ethyl-9-fluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0270](5R)-12-(3,5-difluorophenyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0271](5R)-5-ethyl-9-fluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0272](5R)-12-chloro-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0273](5R)-5-ethyl-9-fluoro-12-(3-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0274](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(4-trifluoromethylphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0275](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0276] (5R)-12-(2-ethoxyethyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0277] or the salts thereof.

[0278] The invention especially relates to compounds of general formula(HCPT)

[0279] in racemic or enantiomeric form or any combinations of theseforms, in which

[0280] R₁ represents a lower alkyl, a lower alkenyl, a lower alkynyl, alower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio loweralkyl;

[0281] R₂, R₃ and R₄ represent, independently, H, halo, lower haloalkyl,lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lowernitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl,azido, lower azidoalkyl, -(CH₂)_(m)NR₆R₇, —(CH₂)_(m)OR6, —(CH₂)_(m)SR6,—(CH₂)_(m)CO₂R6, —(CH₂)_(m)NR6C(O)R₈, —(CH₂)_(m)C(O)R₈,—(CH₂)_(m)OC(O)R₈, —O(CH₂)_(m)NR6R7, —OC(O)NR6R7, OC(O)(CH₂)_(m)CO₂R6 or(CH₂)_(n)[N═X], OC(O)[N═X], (CH₂)_(m)OC(O)[N═X] (in which [N═X], in thisinvention, represents a heterocyclic group with 4 to 7 members with thenitrogen atom N, which is a member of the heterocyclic group, and Xrepresents the remaining members, which are necessary to complete theheterocylic group, selected from the group constituted by O, S, CH₂, CH,N, NR₉ and COR₁₀), substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup or the heterocycle), in which the substituent is a lower alkyl,halo, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl, or R₂ and R₃form together a chain with 3 or 4 members in which the elements of thechain are selected from the group constituted by CH, CH₂, O, S, N orNR9;

[0282] R₅ represents H, halo, lower haloalkyl, lower alkyl, loweralkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl,cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower alkyl lowersulphonylalkyl, lower hydroxyalkyl, nitro, (CH₂)_(m)C(O)R₈,(CH₂)_(m)NR6C(O)R₈, (CH₂)_(m)NR6R7, (CH₂)_(m)N(CH₃)(CH₂)_(n)NR6R7,(CH₂)_(m)OC(O)R₈, (CH₂)_(m)OC(O)NR6R7,(CH₂)_(m)S(O)_(q)R₁₁,(CH₂)_(m)P(O)R₁₂R₁₃, (CH₂)₂P(S)R₁₂R₁₃, substitutedor non-substituted (CH₂)_(n)[N═X] radical, OC(O)[N═X],(CH₂)_(m)OC(O)[N═X], substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the aryl orheteroaryl group), in which the substituent is a lower alkyl, halo,hydroxy, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

[0283] R6 and R7 represent, independently, H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

[0284] R₈ represents H, a lower alkyl, lower hydroxyalkyl, amino, loweralkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl,cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

[0285] R₉ represents H, a lower alkyl, lower haloalkyl, aryl, lowerarylalkyl, or aryl or lower arylalkyl in which the aryl group issubstituted by one or more groups chosen from the following radicals:lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl,lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

[0286] R₁₀ represents H, a lower alkyl, lower haloalkyl, lower alkoxy,aryl or aryl substituted (i.e. having one to four substituents on thearyl group) by one or more groups chosen from the following radicals:lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy loweralkyl;

[0287] R₁₁ represents a lower alkyl, aryl, (CH₂)_(m)OR₁₄, (CH₂)_(m)SR₁₄,(CH₂)₂NR₁₄R₁₅ or (CH₂)_(m)[N═X];

[0288] R₁₂ and R₁₃ represent, independently, a lower alkyl, aryl, loweralkoxy, aryloxy or amino;

[0289] R₁₄ and R₁₅ represent, independently, H, lower alkyl or aryl;

[0290] R₁₈ and R₁₉ represent, independently, H, halo, lower alkyl, loweralkoxy or hydroxy;

[0291] R₂₀ represents H or halo;

[0292] R₂₁ represents H, a lower alkyl, CHO or C(O)(CH₂)_(m)CH₃;

[0293] R_(p) represents H or an easily cleavable group preferably chosenfrom the groups corresponding to the formula —C(O)—A—NR₂₂R₂₃, in which Arepresents a linear or branched alkylene radical optionally substitutedby a radical chosen from the free, esterified or salified hydroxy,halogen, free, esterified or salified carboxy, amino, mono ordialkylamino radicals, while R₂₂ and R₂₃, independently, represent H, alower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, loweraminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, loweralkoxy lower alkyl, lower haloalkyl, or substituted or non substitutedaryl or lower arylalkyl (i.e., substituted one to four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

[0294] m is an integer comprised between 0 and 6;

[0295] n is 1 or2; and

[0296] q represents an integer from 0 to 2; and

[0297] [N═X] represents a heterocyclic group with 4 to 7 members, Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀;

[0298] or pharmaceutically acceptable salts thereof.

[0299] For the compounds of general formulae (B1), (B2) and (HCPT) (andin extenso the compounds of general formulae (I) and (II)), thefollowing preferences apply independently to the substituents:

[0300] R₁ represents a lower alkyl, and preferably ethyl;

[0301] R₂ represents halo;

[0302] R₃ represents halo, lower alkyl or lower haloalkyl; when R₃ is alower alkyl, R₃ is preferably methyl or ethyl;

[0303] R₅ represents halo, lower alkyl, lower haloalkyl, loweraminoalkyl, substituted or non substituted (CH₂)_(n)[N═X] radical,substituted or non substituted aryl or lower arylalkyl; preferred(CH₂)_(n)[N═X] radicals include lower alkyl, and piperazines, especiallymethyl substituted piperazines;

[0304] R₁₈ and R₁₉ represent H.

[0305] R₂₀ represents H.

[0306] The invention particularly relates to the following compoundswhich are described as examples of compounds responding to the generalformula (B1) or the general formula (B2):

[0307] tert-butyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate;

[0308] ethyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate;

[0309]5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0310] 3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoic acid;

[0311] methyl 3-hydroxy-3-[8-(methoxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

[0312] ethyl 2,2-difluoro-3-hydroxy-3-[8-(hydroxymethyl)-9 oxo 9,11dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate;

[0313] ethyl3-hydroxy-3-(8-methyl-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl)pentanoate;

[0314] tert-butyl3-{8-[(acetyloxy)methyl]-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl}-3-hydroxypentanoate;

[0315]5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0316] 3-[12-ethyl-8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7yl]-3-hydroxpentanoic acid;

[0317]8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

[0318]10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0319]3-[2-(benzyloxy)-8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]-3-hydroxypentanoicacid (E);

[0320]5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0321] 11-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0322]5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0323]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0324]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0325]7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione;

[0326]9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0327]5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0328] 9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0329]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0330]5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0331]10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0332]9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0333] 5-ethyl-5,10-dihydroxy-11-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0334]5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0335] 5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0336]9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0337]9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0338]5-ethyl-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0339]5-ethyl-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0340]5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0341]5-ethyl-10-fluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0342]5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0343]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0344]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0345]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0346]8-ethyl-8-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

[0347]9-chloro-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0348]12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0349]5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0350]5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0351]5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0352]5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0353]12-[(dimethylamino)methyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0354]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0355]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0356]12-{[benzyl(methyl)amino]methyl}-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0357]12-[(4-benzyl-1-piperazinyl)methyl]-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[0358]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0359]12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0360]12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0361]12-[(dimethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0362]12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0363]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0364]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0365]12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0366]12-[(diisobutylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0367]5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0368]5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0369]9-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0370]9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0371]12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0372]5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0373]5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0374]5-ethyl-5-hydroxy-10-methoxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0375]12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0376]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0377]10-(benzyloxy)-5-ethyl-9-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0378]5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0379]5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl2-aminoacetate;

[0380]5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl3-aminopropanoate;

[0381]2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0382]9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0383]2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0384]2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0385](+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0386](+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]-4-methyl-hexahydropyridine;

[0387] or a pharmaceutically acceptable salt thereof.

[0388] The invention more particularly relates to the followingcompounds corresponding to the formula (HCPT):

[0389]5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;

[0390]5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0391]8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

[0392]10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0393]5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0394]11-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0395]5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0396]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0397]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0398]7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione;

[0399]9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0400]5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0401]9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0402]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0403]5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0404]10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0405]9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0406]5-ethyl-5,10-dihydroxy-11-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0407]5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0408]5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0409]9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0410]9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0411]5-ethyl-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15Hoxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0412]5-ethyl-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0413]5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0414]5-ethyl-10-fluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0415]5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0416]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0417]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0418]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0419]8-ethyl-8-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

[0420]9-chloro-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0421]12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0422]5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0423]5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0424]5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0425]5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0426]12-[(dimethylamino)methyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0427]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0428]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0429]12-{[benzyl(methyl)amino]methyl}-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0430]12-[(4-benzyl-1-piperazinyl)methyl]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0431]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0432]12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0433]12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0434]12-[(dimethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0435]12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0436]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0437]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0438]12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0439]12-[(diisobutylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0440]5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0441]5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0442]9-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0443]9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0444]12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0445]5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0446]5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0447]5-ethyl-5-hydroxy-10-methoxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0448] 12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-5-hydroxy- I0-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0449]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0450]10-(benzyloxy)-5-ethyl-9-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0451]5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0452]5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinolin-5-yl2-aminoacetate;

[0453]5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinolin-5-yl3-aminopropanoate;

[0454] 2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0455] 9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0456]2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0457]2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0458](+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0459](+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;

[0460](5R)-5-ethyl-11-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0461](5R)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0462](5R)-12-benzyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0463](5R)-12-butyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0464](5R)-5,12-diethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0465](5R)-5-ethyl-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0466](5R)-12-cyclohexyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0467](5R)-5-ethyl-5-hydroxy-12-(4-methylphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0468](5R)-10-chloro-5-ethyl-12-(2-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0469](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0470](5R)-5-ethyl-9-fluoro-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0471](5R)-12-butyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0472](5R)-12-benzyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0473](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0474](5R)-5,12-diethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0475](5R)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0476](5R)-12-butyl-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0477](5R)-5,12-diethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0478](5R)-5-ethyl-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0479](5R)-12-butyl-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0480](5R)-5,12-diethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0481](5R)-5-Ethyl-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0482](5R)-5-ethyl-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0483](5R)-12-(2,6-difluorophenyl)-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0484](5R)-12-(3,5-difluorophenyl)-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0485](5R)-5-ethyl-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0486](5R)-5-ethyl-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0487](5R)-5-ethyl-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0488](5R)-5-ethyl-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0489](5R)-5-ethyl-9-fluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0490](5R)-12-(2,6-difluorophenyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0491](5R)-12-(3,5-difluorophenyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0492](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0493](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0494](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0495](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0496](5R)-5-ethyl-9,10-difluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0497](5R)-12-(2,6-difluorophenyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0498](5R)-12-(3,5-difluorophenyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0499](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0500](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0501](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0502](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0503](5R)-5-ethyl-9,11-difluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0504](5R)-12-(2,6-difluorophenyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0505](5R)-12-(3,5-difluorophenyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0506](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0507](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0508](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0509](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0510](5R)-5-ethyl-9-fluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0511](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(3,3,3-trifluoropropyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0512](5R)-5-ethyl-9-fluoro-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0513](5R)-5-ethyl-9-fluoro-5-hydroxy-12-pentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0514](5R)-5-ethyl-9-fluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0515](5R)-12-(2-cyclohexylethyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0516](5R)-12-(3,3-dimethylbutyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0517](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0518](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(3,3,3-trifluoropropyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0519](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0520](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-pentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0521](5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0522](5R)-12-(2-cyclohexylethyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0523](5R)-12-(3,3-dimethylbutyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0524](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0525](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(3,3,3-trifluoropropyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0526](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0527](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-pentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0528](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0529](5R)-12-(2-cyclohexylethyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0530](5R)-12-(3,3-dimethylbutyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0531](5R)-12-chloro-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0532](5R)-5-ethyl-5-hydroxy-12-hydroxymethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0533](5R)-5-ethyl-9-fluoro-5-hydroxy-12-isobutyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0534](5R)-5-ethyl-9-fluoro-5-hydroxy-12-neopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0535](5R)-5-ethyl-9-fluoro-12-(3-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0536](5R)-5-ethyl-9-fluoro-5-hydroxy-12-(4-trifluoromethylphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0537](5R)-12-[4-(tert-butyl)phenyl]-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0538](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0539](5R)-12-(2-ethoxyethyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione;

[0540](5R)-5-ethyl-9,10,11-trifluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione.

[0541] or pharmaceutically acceptable salts thereof.

[0542] Among the above list of compounds, the following are preferred:

[0543]5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;

[0544]5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0545]8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

[0546]5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0547]5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0548]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0549]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0550]7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione;

[0551]9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0552]5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0553]9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0554]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0555]5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0556]10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0557]9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0558]5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0559]5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0560]5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0561]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0562]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0563]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0564]12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0565]5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0566]5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0567]5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0568]5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0569]12-[(dimethylamino)methyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0570]9-chloro-5-ethyl-5-hydroxy-10-methyl-2-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0571]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0572]12-[(4-benzyl-1-piperazinyl)methyl]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0573]12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0574]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0575]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0576]12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0577]12-[(diisobutylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0578]5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0579]9-chloro-12-[(dimethylamino)methyl]5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0580]9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0581]5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0582]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0583]5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0584]2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0585]9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0586]2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0587]2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0588](+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0589](+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;

[0590] or a pharmaceutically acceptable salt thereof.

[0591] Among the above list of compounds, the following are morepreferred:

[0592]5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;

[0593]5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0594]8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione;

[0595]5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0596]5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0597]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0598]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0599]7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione;

[0600]9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0601]5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0602]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0603]5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0604]10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0605]9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0606]5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0607]5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0608]5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0609]5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0610]5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0611]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0612]9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0613]12-[(diethylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0614]5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0615]12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0616]5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0617]5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0618]2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0619]9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0620]2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0621]2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione;

[0622](+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0623](+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;

[0624] or a pharmaceutically acceptable salt thereof.

[0625] Among the above lists of compounds, particularly preferredcompounds for the present invention are the following:

[0626]5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione;

[0627]5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0628]5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0629]5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0630](+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione;

[0631](+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine

[0632] or a pharmaceutically acceptable salt of the latter.

[0633] Among the above lists of compounds, more particularly preferredcompounds for the present invention are the following:

[0634] (+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0635](+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]-4-methyl -hexahydropyridine;

[0636] or a pharmaceutically acceptable salt of the latter.

[0637] A more particular subject of the invention is the compounds ofgeneral formula (I) and general formula (II),

[0638] in racemic or enantiomeric form or any combinations of theseforms, in which

[0639] R₁ represents a lower alkyl, a lower alkenyl, a lower alkynyl, alower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio loweralkyl;

[0640] R₂, R₃ and R₄ represent, independently, H, halo, lower haloalkyl,lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lowernitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl,azido, lower azidoalkyl, (CH₂)_(m)NR6R7, (CH₂)_(m)OR6, (CH₂)_(m)SR6,(CH₂)_(m)CO₂R6, (CH₂)_(m)NR6C(O)R₈, (CH₂)_(m)C(O)R₈, (CH₂)_(m)OC(O)R₈,O(CH₂)_(m)NR6R7, OC(O)NR6R7, OC(O)(CH₂)_(m)CO₂R6 or (CH₂)_(n)[N═X],OC(O)[N═X], (CH₂)_(m)OC(O)[N═X] (in which[N═X], in this invention,represents a heterocyclic group with 4 to 7 members with the nitrogenatom N, which is a member of the heterocyclic group, and X representsthe remaining members, which are necessary to complete the heterocylicgroup, selected from the group constituted by O, S, CH₂, CH, N, NR₉ andCOR₁₀), substituted or non substituted aryl or lower arylalkyl (i.e.substituted between once and four times on the aryl group or theheterocycle), in which the substituent is a lower alkyl, halo, nitro,amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, loweralkoxy or lower alkoxy lower alkyl) or R₂ and R₃ form together a chainwith 3 or 4 members in which the elements of the chain are selected fromthe group constituted by CH, CH₂, O, S, N or NR₉;

[0641] R₅ represents H, halo, lower haloalkyl, lower alkyl, loweralkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl,cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower alkyl lowersulphonylalkyl, lower hydroxyalkyl, nitro, (CH₂)_(m)C(O)R₈,(CH₂)_(m)NR6C(O)R₈, (CH₂)_(m)NR6R7, (CH₂)_(m)N(CH₃)(CH₂)_(n)NR6R7,—(CH₂)_(m)OC(O)R₈, (CH₂)_(m)OC(O)NR6R7, (CH₂)_(m)S(O)_(q)R₁₁,(CH₂)_(m)P(O)R₁₂R₁₃, (CH₂)₂P(S)R₁₂R₁₃ or (CH₂)_(n)[N═X], OC(O)[N═X],(CH₂)_(m)OC(O)[N═X], substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the aryl orheteroaryl group), in which the substituent is a lower alkyl, halo,nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl,lower alkoxy or lower alkoxy lower alkyl;

[0642] R6 and R7 represent, independently, H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

[0643] R₈ represents H, a lower alkyl, lower hydroxyalkyl, amino, loweralkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl,cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

[0644] R₉ represents H, a lower alkyl, lower haloalkyl, aryl, lowerarylalkyl, or aryl or lower arylalkyl in which the aryl group issubstituted by one or more groups chosen from the following radicals:lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl,lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

[0645] R₁₀represents H, a lower alkyl, lower haloalkyl, lower alkoxy,aryl or aryl substituted (i.e. having one to four substituents on thearyl group) by one or more groups chosen from the following radicals:lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy loweralkyl;

[0646] R₁₁ represents a lower alkyl, aryl, (CH₂)_(m)OR₁₄, (CH₂)_(m)SR₁₄,(CH₂)₂NR₁₄R₁₅ or (CH₂)_(m)[N═X];

[0647] R₁₂ and R₁₃ represent, independently, a lower alkyl, aryl, loweralkoxy, aryloxy or amino;

[0648] R₁₄ and R₁₅ represent, independently, H, lower alkyl or aryl;

[0649] R₁₆ represents H or OR₂₁;

[0650] R₁₇ represents —OR6 or —NR6R7;

[0651] R₁₈ and R₁₉ represent, independently, H, halo, lower alkyl, loweralkoxy or hydroxy;

[0652] R₂₀ represents H or halo;

[0653] R₂₁ represents H, a lower alkyl, CHO or C(O)(CH₂)_(m)CH₃;

[0654] m is an integer comprised between 0 and 6;

[0655] n is 1 or 2; and

[0656] q represents an integer from 0 to 2; and

[0657] [N═X] represents a heterocyclic group with 4 to 7 members, Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀:

[0658] or a pharmaceutically acceptable salt thereof.

[0659] A particular subject of the invention is the compounds offormulae I and II as defined above in which R₁ represents a lower alkyl,lower alkenyl, lower haloalkyl, lower alkoxy lower alkyl or loweralkylthio lower alkyl; R₅ represents H, halo, lower haloalkyl, loweralkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio loweralkyl, cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lowerhydroxyalkyl, nitro, —(CH₂)_(m)C(O)R₈, —(CH₂)_(m)NR6C(O)R₈,—(CH₂)_(m)NR6R7, —(CH₂)_(m)N(CH₃)(CH₂)_(n)NR6R7, —(CH₂)_(m)OC(O)R₈,—(CH₂)_(m)OC(O)NR6R7, or (CH₂)_(n)[N═X], OC(O)[N═X],(CH₂)_(m)OC(O)[N═X], substituted or non substituted aryl or lowerarylalkyl; R₁₂ and R₁₃ represent, independently, a lower alkyl; R₁₆represents OR₂₁; and R₁₈, R₁₉ and R₂₀ represent H.

[0660] The invention has more particularly as its subject matter thecompounds of formula (I) and (II) as is defined above in which R₁represents a lower alkyl, lower alkenyl, lower haloalkyl or lower alkoxylower alkyl; R₂, R₃ and R₄ represent, independently, H, halo, lowerhaloalkyl, lower alkyl, nitro, amido, lower amidoalkyl, hydrazino, lowerhydrazinoalkyl, azido, lower azidoalkyl, —(CH₂)_(m)NR6R7, —(CH₂)_(m)OR6,—(CH₂)_(m)SR6, —(CH₂)_(m)C(O)R₈, —(CH₂)_(n)[N═X], or—(CH₂)_(m)OC(O)[N═X] substituted or non substituted, or OC(O)[N═X]; orR₂ and R₃ form together a chain with 3 or 4 members in which theelements of the chain are selected from the group constituted by CH,CH₂, O, S, N or NR₉; R₅ represents H, halo, lower haloalkyl, loweralkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio loweralkyl, lower hydroxyalkyl, nitro, —(CH₂)_(m)C(O)R₈, —(CH₂)_(m)NR6C(O)R₈,—(CH₂)_(m)NR6R7, —(CH₂)_(m)N(CH₃)(CH₂)_(n)NR6R7, —(CH₂)_(m)OC(O)R8 ,—(CH₂)_(m)OC(O)NR6R7, or (CH₂)_(n)[N═X], OC(O)[N═X] substituted or nonsubstituted or (CH₂)_(m)OC(O)[N═X]; R6 and R7 represent, independently,H, a lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl,lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl; R₈ represents H, a lower alkyl, lower hydroxyalkyl, loweralkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl,cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl; R₉ represents H, a lower alkyl or lower haloalkyl; R₁₀represents H, a lower alkyl, lower haloalkyl or lower alkoxy; R₉represents H or lower alkyl; and R₁₄ and R₁₅ represent, independently, Hor lower alkyl.

[0661] In a more preferred manner, R₂ represents H or halo andpreferably H, chloro or fluoro; and R₃ represents H, a lower alkyl, haloor OR6 in which R6 represents H, a lower alkyl or a lower arylalkyl andpreferably H, fluoro, chloro, methyl or methoxy. Also in a morepreferred manner, R₂ and R₃ together form a methylenedioxy or anethylenedioxy.

[0662] A more particular subject of the invention is the compounds offormula (I) and (II) for which R₂ represents a hydrogen or halogen atom,R₃ represents a halogen atom, a lower alkyl or a lower alkoxy, R₄ andR₁₆ represent hydrogen atoms, and R₁₈, R₁₉ and R₂₀ represent hydrogenatoms; or a pharmaceutically acceptable salt of the latter. Anaminoalkyl radical will then preferably be chosen for R₅.

[0663] A more particular subject of the invention is the productsdescribed hereafter in the examples and corresponding to the followingformulae:

[0664]5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(1,2,5,6-tetrahydopyridinomethyl-1H -oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dionehydrochloride

[0665] 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0666]5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-pyrrolidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0667] 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperazinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0668]5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-piperidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0669]5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-dimethylamino-methyl-1H-oxepino(3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0670] 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-morpholinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0671]9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperazinomethyl)-1H-oxepino(3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0672]12-benzylpiperazinomethyl-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-1H -oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0673]12-(4-benzylpiperazinomethyl)-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0674]9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-piperidinomethyl-1H-oxepino(3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0675]12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0676]12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0677]5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-dimethylaminomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0678]5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0679] 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0680]5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0681]5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(1,2,5,6-tetrahydropyridinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0682]12-diisobutylaminomethyl-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0683]5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperazinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0684] 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0685] 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-dimethylaminomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0686] 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dionehydrochloride

[0687]5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(1,2,5,6-tetrahydropyridinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H13H)-dionehydrochloride

[0688] 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0689] 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperazinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H 13H)-dione

[0690] 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-pyrrolidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0691]12-(4-benzylpiperazinomethyl)-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

[0692]9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(-4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

[0693] 10-benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

[0694]5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

[0695] or a pharmaceutically acceptable salt of the latter.

[0696] A more particular subject of the invention is the compounds offormula (I) as defined above, in which R₁ represents the ethyl group; R₂and R₃ represent, independently, H, a lower alkyl, halo, lower alkylhalo or (CH₂)_(m)OR6, or R₂ and R₃ form together a methylenedioxy or anethylenedioxy; R₄ and R₅ represent, independently, H, a lower alkyl,(CH₂)_(m)NR6R7, or (CH₂)_(n)[N═X] non substituted or substituted by alower alkyl; R₂₀ represents H and R₁₇ represents OR6, in which R6represents H or a lower alkyl, or NR6R7 in which R6 and R7,independently, represent H, a lower alkyl, aryl or lower alkyl aryl.Preferably, R₄ represents H or (CH₂)_(m)NR6R7, in which R6 and R7represent, independently, H or a lower alkyl ; R₅ represents H, a loweralkyl or —(CH₂)_(n)[N═X] non substituted or substituted by a loweralkyl; and R₁₇ represents OR6 in which R6 represents H or a lower alkyl;or a pharmaceutically acceptable salt of the latter. As an example ofsubstituted or non substituted[N═X], there can be mentioned thepiperidyl, morpholinyl, piperazinyl, imidazolyl and 4-methylpiperazinylradical.

[0697] In a more preferred manner, R₂ represents H or halo andpreferably H, chloro or fluoro; R₃ represents H, a lower alkyl, halo or—OR6 in which R6 represents H, a lower alkyl or a lower alkyl aryl andpreferably H, fluoro, chloro, methyl or methoxy. Also in a morepreferred manner R₂ and R₃ form together dioxymethylene ordioxyethylene.

[0698] A more particular subject of the invention is the productsdescribed hereafter in the examples, in particular the productscorresponding to the following formulae:

[0699] 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

[0700]5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

[0701] 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl -12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

[0702]5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

[0703]9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dionehydrochloride;

[0704] 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

[0705]9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

[0706] or a pharmaceutically acceptable salt thereof.

[0707] Camptothecin and certain of its analogues are not hydrosoluble,which makes their administration by parenteral route difficult.Hydrosoluble derivatives of camptothecin have been prepared where ringsA and B carry salifiable substituents (cf. for example U.S. Pat. Nos.4,981,968, 5,049,668, EP 540,099). However, these products revealed anantitumoral activity which was reduced with respect to that ofnon-hydrosoluble derivatives. Other hydrosoluble derivatives ofcamptothecin have also been prepared where the hydroxyl group inposition 20 is esterified by an acid carrying a salifiable radical suchas for example glycine (cf. U.S. Pat. No. 4,943,579 and PCT No. WO96/02546). These derivatives are designated by a person skilled in theart under the name “prodrug forms” as they are not biologically activein themselves, but only after a first metabolization phase onceadministered to the patient. The prodrug forms of the α-hydroxylactoneanalogues of camptothecin have shown a good anti-tumoral effectivenessin animals and clinically, but accompanied by damaging side-effects suchas the appearance of serious diarrhoeas which can put the patient's lifein danger. It is therefore necessary to develop hydrosoluble analoguesof camptothecin which are more effective and better tolerated.

[0708] Hydrosolubility of the camptothecin analogues being important,some compounds according to the present invention have also beendesigned in order to possess this property as well.

[0709] Two solutions were chosen in order to increase thehydrosolubility of the camptothecin analogues: the first consists ingrafting an oxazine onto the A ring of the molecule, and the second indesigning prodrug forms by acetylating the hydroxy function of theβ-hydroxylactone.

[0710] More specifically, among this new class of camptothecinanalogues, the compounds according to the present invention are eitheranalogues modified by fixation of an oxazine ring on carbons 10 and 11or prodrug forms in which a β-hydroxylactone replaces the naturalα-hydroxylactone of camptothecin. The compounds of the present inventionare therefore camptothecin analogue β-hydroxylactones on which anoxazine ring or hydrosoluble prodrugs have been grafted and present apowerful biological activity which is unexpected in the light of thestate of the prior art.

[0711] Another object of the invention is therefore the compounds offormula (I)_(OP) and formula (II)_(OP):

[0712] in racemic or enantiomeric form or any combinations of theseforms, in which

[0713] R₁ represents a lower alkyl, a lower alkenyl, a lower alkynyl, alower haloalkyl, a lower alkoxy lower alkyl or lower arlkyl;

[0714] R₂, R₃ and R₄ represent, independently, H, halo, lower haloalkyl,lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lowernitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl,azido, lower azidoalkyl, (CH₂)_(m)NR6R7, (CH₂)_(m)OR6, (CH₂)_(m)SR6,(CH₂)_(m)CO₂R6, (CH₂)_(m)NR6C(O)R₈, (CH₂)_(m)C(O)R₈, (CH₂)_(m)OC(O)R₈,O(CH₂)_(m)NR6R7, OC(O)NR6R7, OC(O)(CH₂)_(m)CO₂R6 or (CH₂)_(n)[N═X],OC(O)[N═X], (CH₂)_(m)OC(O)[N═X] (in which[N═X], in this invention,represents a heterocyclic group with 4 to 7 members with the nitrogenatom N, which is a member of the heterocyclic group, and X representsthe remaining members, which are necessary to complete the heterocylicgroup, selected from the group constituted by O, S, CH₂, CH, N, NR₉ andCOR₁₀), aryl or lower arylalkyl substituted (i.e. substituted betweenonce and four times on the aryl group or the heterocycle) or nonsubstituted, in which the substituent is a lower alkyl, halo, nitro,amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, loweralkoxy or lower alkoxy lower alkyl or R₂ and R₃ or R₃ and R₄ formtogether a chain with 3 or 4 members in which the elements of the chainare selected from the group constituted by CH, CH₂, O, S, N or NR₉;

[0715] R₅ represents H, halo, lower haloalkyl, lower alkyl, loweralkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl,cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower alkyl lowersulphonylalkyl, lower hydroxyalkyl, nitro, (CH₂)_(m)C(O)R₈,(CH₂)_(m)NR6C(O)R₈, (CH₂)_(m)NR6R7, (CH₂)_(m)N(CH₃)(CH₂)_(n)NR6R7,(CH₂)_(m)OC(O)R₈, (CH₂)_(m)OC(O)NR6R7, (CH₂)_(m)S(O)_(q)R₁₁,(CH₂)_(m)P(O)R₁₂R₁₃ (CH₂)₂P(S)R₁₂R₁₃ or (CH₂)_(n)[N═X], OC(O)[N═X],(CH₂)_(m)OC(O)[N═X], substituted or non substituted aryl or lower alkylaryl (i.e. substituted between once and four times on the aryl orheteroaryl group), in which the substituent is a lower alkyl, halo,nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl,lower alkoxy or lower alkoxy lower alkyl;

[0716] R6 and R7 represent, independently, H, a lower alkyl, lowerhydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy loweralkyl, lower haloalkyl, or a substituted or non substituted aryl orlower arylalkyl (i.e. substituted between once and four times on thearyl group), in which the substituent is a lower alkyl, halo, nitro,amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, loweralkoxy or lower alkoxy lower alkyl;

[0717] R₈ represents H, a lower alkyl, lower hydroxyalkyl, amino, loweralkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl,cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy loweralkyl, lower haloalkyl, or substituted or non substituted aryl or lowerarylalkyl (i.e. substituted between once and four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

[0718] R₉ represents H, a lower alkyl, lower haloalkyl, aryl, lowerarylalkyl, or aryl or lower arylalkyl in which the aryl group issubstituted by one or more groups chosen from the following radicals:lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl,lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

[0719] R₁₀ represents H, a lower alkyl, lower haloalkyl, lower alkoxy,aryl or aryl substituted (i.e. having one to four substituents on thearyl group) by one or more groups chosen from the following radicals:lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy loweralkyl;

[0720] R₁₁ represents a lower alkyl, aryl, (CH₂)_(m)OR₁₄, (CH₂)_(m)SR₁₄,(CH₂)₂NR₁₄R₁₅ or (CH₂)_(m)[N═X];

[0721] R₁₂ and R₁₃ represent, independently, a lower alkyl, aryl, loweralkoxy, aryloxy or amino;

[0722] R₁₄ and R₁₅ represent, independently, H, lower alkyl or aryl;

[0723] R₁₆ represents H or OR₂₁;

[0724] R₁₇ represents OR6 or NR6R7;

[0725] R₁₈ and R₁₉ represent, independently, H, halo, lower alkyl, loweralkoxy or hydroxy;

[0726] R₂₀ represents H or halo;

[0727] R₂₁ represents H, a lower alkyl, CHO or C(O)CH₂)_(m)CH₃;

[0728] R_(p) represents H or an easily cleavable group preferably chosenfrom the groups corresponding to the formula —C(O)—A—NR₂₂R₂₃, in which Arepresents a linear or branched alkylene radical optionally substitutedby a radical chosen from the free, esterified or salified hydroxy,halogen, free, esterified or salified carboxy, amino, mono ordialkylamino radicals, while R₂₂ and R₂₃, independently, represent H, alower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, loweraminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, loweralkoxy lower alkyl, lower haloalkyl, or substituted or non substitutedaryl or lower arylalkyl (i.e., substituted one to four times on the arylgroup), in which the substituent is a lower alkyl, halo, nitro, amino,lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy orlower alkoxy lower alkyl;

[0729] m is an integer comprised between 0 and 6;

[0730] n is 1 or 2; and

[0731] q represents an integer from 0 to 2; and

[0732] [N═X] represents a heterocyclic group with 4 to 7 members, Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S, CH₂, CH, N, NR₉ and COR₁₀;

[0733] it being understood that when Rp is a hydrogen atom, R₃ and R₄together form a chain with 3 or 4 members;

[0734] or a pharmaceutically acceptable salt thereof.

[0735] As concerns the oxazin-grafted forms of the invention, R₂preferably represents a radical chosen from the group consisting of H,halo or lower alkyl.

[0736] As concerns the prodrug forms of the invention (those for whichR_(p) is not a hydrogen atom), the products of general formula (I)_(OP)are preferred. Preferably, R₂ and R₃ then represent, independently, aradical chosen from the group consisting of halo or lower alkyl.

[0737] Examples of substituted camptothecins used as starting productscan be found in the U.S. Pat. Nos. 4,473,692, 4,604,463, 4,894,956,5,162,532, 5,395,939, 5,315,007, 5,264 579, 5,258,516, 5,254,690,5,212,317 and 5,341,745, the PCT Patent Applications Nos. US91/08028,US94/06451, US90/05172, US92/04611, US93/10987, US91/09598, EP94/03058and EP95/00393 and the European Patent Application Nos. 325 247, 495432, 321 122 and 540 099.

[0738] For the compounds comprising an oxazine ring:

[0739] a β-hydroxylactonic compound of general formula D

[0740] in which R₃ is a hydroxyl radical, R₄ is H and R₁, R₂, R₅, R₁₈,R₁₉ and R₂₀ have the meaning indicated above is treated with a primaryamine, under Mannich's conditions, in order to obtain aβ-hydroxylactonic compound of general formula Ia

[0741] in which R₁, R₂, R₅, R₉, R₁₈, R₁₉ and R₂₀ have the meaningindicated above.

[0742] This process consists in heating the starting product in thepresence of a primary amine such as benzylamine, of formaldehyde in anacid solvent such as acetic acid or propionic acid at a temperature of30° C. to 80° C. for a period of 0.5 to 5 hours. Alternatively, asuspension of starting product in acetic acid with a tri-N-substitutedhexahydrotriazine such as hexahydro-1,3,5-trimethyl triazine,1,3,5-triethylhexahydro triazine or 1,3,5-tribenzyl hexahydrotriazinecan be heated at a temperature of 30° C. to 80° C. for a period of 0.5to 5 hours.

[0743] the lactone of general formula Ia is opened optionally in a basicmedium in order to produce after neutralization the compound of formulaIIa

[0744] in which R₁, R₂, R₅, R₉, R₁₇, R₁₈, R₁₉ and R₂₀ have the meaningindicated above; R₁₆ represents OR₂₁ in which R₂₁ represents H or alower alkyl; and R₁₇ represents OR′6 or NHR′6 and R′6 represents H, alower alkyl, cycloalkyl, lower cycloalkyl alkyl, lower alkenyl, loweralkoxy lower alkyl, or aryl or lower aryl alkyl.

[0745] the said compound of general formula D or Ia is optionallyacylated, preferably with a derivative of the C(O)—A—N—R₂₂R₂₃ radical asdefined above in order to produce the β-hydroxylactonic compound ofgeneral formula Ib, i.e. (I)_(OP) with R_(p) different from H (prodrugform of the invention).

[0746] in the same manner as with the lactone Ia, the lactone Ib can beopened in order to produce hydroxyacid IIb.

[0747] The opening of the lactone ring in a basic medium can moregenerally be used in order to convert products of general formula (B1)in products of general formula (B2).

[0748] In the above process, the R₂, R₃, R₄ and R₅ groups can beprotected if necessary according to standard protection methods (Greene,T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons1981)). If at least one of the R₂₂ or R₂₃ groups is H, or contains atleast one function which is chemically incompatible with the acylationprocess such as, for example, a primary or secondary amine, it is thennecessary to use a protective group which is resistent to acylationconditions. A protective group commonly used for the amines istert-butyloxycarbonyl (BOC). The acylation reaction is then carried outas described above, then the protective group is cleaved, for example bytreatment with trifluoroacetic acid in the case of BOC, in order toproduce the compound of general formula (I) or (II). Use of protectivegroups is known to a person skilled in the art (for other examples,reference can be made to Greene, T., Protective Groups in OrganicSynthesis, John Wiley & Sons, 1981).

[0749] The preparation of the compounds of general formula D isdescribed later in the present application.

[0750] As it is used here, the term lower with reference to the alkyl,alkylthio and alkoxy groups designates linear or branched saturatedaliphatic hydrocarbon groups containing 1 to 6 carbons, such as forexample, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methylthio,ethylthio, methoxy and ethoxy. With reference to the alkenyl or alkynylgroups, the term lower designates groups containing 2 to 6 carbon atomsand one or more double or triple bonds, such as for example, the vinyl,allyl, isopropenyl, pentenyl, hexanyl, ethynyl propenyl, propynyl andbutynyl groups. The term cycloalkyl designates a ring with 3 to 7carbons, such as for example, the cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl groups. The term aryl designates a mono- di- or tricyclichydrocarbon compound with at least one aromatic ring, each ringcontaining a maximum of 7 members, such as for example, phenyl,naphthyl, anthracyl, biphenyl or indenyl. The term halo signifieschloro, bromo, iodo or fluoro. The radicals corresponding to theexpressions lower haloalkyl, lower cyanoalkyl, lower nitroalkyl, loweramidoalkyl, lower hydrazinoalkyl, lower azidoalkyl, lower arylalkyl,lower hydroxyalkyl, lower alkoxy lower alkyl, lower alkylthio loweralkyl, and lower alkyl lower sulphonylalkyl are substituted,respectively, by one to three halo, cyano, nitro, amido, hydrazino,azido, aryl, hydroxy, lower alkoxy, lower alkylthio or lowersulphonylalkyl groups. The lower alkylamino radical can contain one ortwo lower alkyl groups and represent, for example, NHCH₃, NHCH₂CH₃,N(CH₃)₂ or N(CH₃)(CH₂CH₃). Examples of [N═X] include the piperidinyl,morpholinyl, piperizinyl and imidazolyl groups.

[0751] As has been observed for camptothecin, the carbon atom carryingthe hydroxy function in the p-hydroxylactone or the β-hydroxycarboxylategroup of the compounds according to the present invention, isasymmetrical. Consequently, the compounds according to the presentinvention have two possible enantiomeric forms, i.e. under “R” and “S”configurations. The present invention includes the two enantiomericforms and any combinations of these forms, including “RS” racemicmixtures. In an effort to simplify matters, when no specificconfiguration is indicated in the structural formulae, it should beunderstood that the two enantiomeric forms and their mixtures arerepresented.

[0752] A subject of the invention is also preparation processes for thecompounds of general formulae (B1) and (B2), either starting withcamptothecin or substituted camptothecins, or by total chemicalsynthesis.

[0753] Therefore the invention relates to a preparation process for thecompounds of formulae (B1) and (B2) according to the invention, and inparticular the products the formulae of which are indicated above,starting with camptothecin or substituted camptothecins characterized inthat:

[0754] camptothecin a-hydroxylactone of general formula

[0755] in which R₁, R₂, R₃, R₄, R₅ and R₂₀ have the meaning indicatedabove, is reduced in order to obtain the α-hydroxylactol of generalformula A

[0756] in which R₁, R₂, R₃, R₄, R₅ and R₂₀ have the meaning indicatedabove,

[0757] in compound A thus formed, the carbon-carbon bond linking theadjacent carbinols, is cut by treatment with an appropriate oxidizingagent so as to produce a compound of formula B

[0758] in which R₁, R₂, R₃, R₄, R₅ and R₂₀ have the meaning indicatedabove,

[0759] then treatment is carried out with a functionalized alkylatingagent and the formyl function of the compound of formula B is cut inorder to produce a β-hydroxyester of general formula C

[0760] in which R₁, R₂, R₃, R₄, R₅, R₁₈, R₁₉ and R₂₀ have the meaningindicated above, and R₁₇ represents OR′6 and R′6 represents a loweralkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxylower alkyl or aryl or lower aryl alkyl;

[0761] said compound of general formula C is cyclized in order toproduce the β-hydroxylactonic compound of general formula D

[0762] in which R₁, R₂, R₃, R₄, R₅, R₁₈, R₁₉ and R₂₀ have the meaningindicated above,

[0763] the lactone of general formula D is opened in order to producethe compound of formula E

[0764] in which R₁, R₂, R₃, R₄, R₅, R₁₇, R₁₈, R₁₉ and R₂₀ have themeaning indicated above; R₁₆ represents OR₂₁ in which R₂₁ represents Hor a lower alkyl; and R₁₇ represents OR′6 or NHR′6 and R′6 represents H,a lower alkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, loweralkoxy lower alkyl or aryl or lower aryl alkyl.

[0765] Certain compounds of general formula E can also be obtained byhydrolysis of the ester function of the corresponding compounds ofgeneral formula D. The compounds of general formula E in which R₁₆and/or R₁₇ represent, independently, the hydroxy radical, can beesterified or amidified under standard conditions known to a personskilled in the art in order to obtain the corresponding esters or amidesof general formula E.

[0766] In the above process, the R₂, R₃, R₄ and R₅ groups can beprotected if necessary according to standard protection methods (Greene,T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons1981)). During this process, the reduction is carried out using areducing agent in an appropriate solvent, such as, for example, sodiumborohydride in methanol. The stage corresponding to the formation ofcompound of general formula B starting from compound of general formulaA is implemented under oxidizing conditions, such as, for example, withlead tetraacetate, periodic acid or sodium metaperiodate in anappropriate solvent, such as, for example, acetic acid. The treatmentwith a functionalized alkylating agent can be implemented using ametallic derivative for example, of lithium or zinc, of a carboxylicester in an anhydrous aprotic solvent such as, for example,tetrahydrofuran. The lactonization stage which allows compound ofgeneral formula D to be obtained starting from compound of generalformula C is generally carried out under acid conditions, such as, forexample, by treatment with trifluoroacetic acid or hydrochloric gasdissolved in an anhydrous solvent such as dichloromethane or dioxan. Theopening of the lactonic ring of compound of general formula D in orderto obtain compound of general formula E, can be carried out, forexample, by hydrolysis under alkaline conditions followed byneutralization.

[0767] Examples of substituted camptothecins used as starting productscan be found in the U.S. Pat. Nos. 4,473,692, 4,604,463, 4,894,956,5,162,532, 5,395,939, 5,315,007, 5,264,579, 5,258,516, 5,254,690,5,212,317 and 5,341,745, the PCT Patent Applications Nos. US91/08028,US94/06451, US90/05172, US92/04611, US93/10987, US91/09598, EP94/03058and EP95/00393 and the European Patent Application Nos. 325,247,495,432, 321,122 and 540,099.

[0768] Therefore, the invention also relates to a preparation processfor the compounds of formulae (B1) and (B2), characterized in that

[0769] a compound of general formula M

[0770] in which R₁, R₁₈ and R₁₉ have the meaning indicated above and R₂₀represents a hydrogen or a halogen atom, is coupled with a2-halo-3-quinoline-methanol of general formula N

[0771] in which R₂, R₃, R₄ and R₅ have the meaning indicated above and Xrepresents a halogen atom, in order to produce the compound of formula O

[0772] in which R₁, R₂, R₃, R₄, R₅, R₁₈, R₁₉, R₂₀ and X have the meaningindicated above;

[0773] then the compound of general formula O is cyclized in order toobtain the compound of general formula D as defined above.

[0774] In the above process, the R₁, R₂, R₃ and R₄ groups can beprotected if necessary according to standard protection methods (Greene.T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons1981)). The formation of compound O starting from the compounds ofgeneral formulae M and N is carried out with a treatment known to aperson skilled in the art under the name Mitsunobu's reaction (refer toMitsunobu, O. et al. Synthesis, p.1 (1981)). The hydroxyl function ofcompound N is displaced by a nucleophile such as compound M or adeprotonated derivative of the latter, by a treatment with a phosphine,for example triphenylphosphine, and an azodicarboxylate derivative, forexample diethyl azodicarboxylate, in an aprotic solvent such as, forexample, tetrahydrofuran or N,N-dimethylformamide. The cyclization ofcompound O is preferably carried out in the presence of a palladiumcatalyst (for example palladium diacetate) under basic conditions(provided for example by an alkaline acetate optionally combined with aphase transfer agent, such as, for example, tetrabutylammonium bromide),in an aprotic solvent such as acetonitrile or N,N-dimethylformamide, ata temperature comprised between 50° C. and 120° C. (R. Grigg et al.,Tetrahedron 46, page 4003 (1990)).

[0775] The compounds of general formula M are new. They can be preparedaccording to a process characterized in that

[0776] the carbonyl of a pyridine of general formula

[0777] n which R₁ and R₂₀ have the meaning indicated above and R₂₂represents a halogen atom or a lower alkoxy, is protected with an acetalfunction, in order to produce the compound of general formula F

[0778] in which R₁, R₂₀ and R₂₂ have the meaning indicated above and theZ and Z′ groups represent, independently, a lower alkyl or form togethera saturated hydrocarbon chain with 2 to 4 carbons:

[0779] a hydroxymethyl function is introduced into the compound ofgeneral formula F in order to obtain a compound of general formula G

[0780] in which R₁, R₂₀, R₂₂, Z and Z′ have the meaning indicated above,

[0781] then the alcohol function of the compound of general formula G isprotected in order to produce a compound of general formula H

[0782] in which R₁, R₂₀, R₂₂, Z and Z′ have the meaning indicated aboveand R₂₃ represents a protective group of the alcohol function.

[0783] the acetal of the compound of general formula H is deprotected inorder to produce the compound of general formula I′

[0784] in which R₁, R₂₀, R₂₂ and R₂₃ have the meaning indicated above,

[0785] the compound of formula I′ is treated with a functionalizedalkylating agent in order to produce a β-hydroxyester of general formulaJ

[0786] in which R₁, R₂₀, R₂₂ and R₂₃ have the meaning indicated above,and R₁₇, R₁₈ and R₁₉ are as defined in general formula II

[0787] the protective group R₂₃ of the compound of general formula J iscleaved in order to produce a compound of general formula K,

[0788] in which R₁, R₁₈, R₁₉, R₂₀ and R₂₂ have the meaning indicatedabove, and R₁₇ represents OR′6 or NHR′6 and R′6 represents H, a loweralkyl, cycloalkyl, lower alkyl cycloalkyl, lower alkenyl, lower alkyllower alkoxy or aryl or lower alkyl aryl,

[0789] the compound of general formula K is cyclized into the compoundof general formula L

[0790] in which R₁, R₁₈, R₁₉, R₂₀ and R₂₂ have the meaning indicatedabove, and finally

[0791] the R₂₂ radical of compound L is converted into carbonyl in orderto obtain the compound of general formula M

[0792] in which R₁, R₁₈, R₁₉, R₂₀, and R₂₂ have the meaning indicatedabove.

[0793] The carbonyl function of a 4-acyl-2-pyridine (obtained forexample according to Lammattina J. L. J. Heterocyclic Chem. 20, p. 553(1983)) is preferably protected by an acetal function, preferably acyclic acetal, according to the standard conditions known to a personskilled in the art (Greene. T., Protective Groups in Organic Synthesis10-86 (John Wiley & Sons 1981)). The intermediate thus obtained istreated with a sodium or potassium alcoholate in an aprotic solvent (forexample acetonitrile), or the alcohol from which the alcoholate isderived, at a temperature comprised between 0° C. and 100° C. in orderto produce the compound of general formula F. The latter can belithiated in position 3 by treatment with an aryl- or alkyl-lithium (forexample mesityl-lithium) in an ethereal solvent such as tetrahydrofuranat a temperature comprised between −100° C. and 0° C. A formylatingelectrophile such as N,N-dimethylformamide is added to the lithiatedintermediate thus obtained, and the aldehyde thus obtained is treated,after hydrolysis, with a reducing agent such as sodium borohydride inorder to produce the compound of general formula G. The protection ofthe alcohol function of compound of general formula G is carried outaccording to the standard conditions known to a person skilled in theart, in order to obtain a compound of general formula H. Examples ofprotective groups of the alcohol function include those which formethers (i.e. methyl, methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, benzyloxymethyl, t-butyl and benzyl (substituted or nonsubstituted)), and esters (i.e. formate, acetate and isobutyrate). Forother examples of protective groups of primary hydroxyls refer toGreene. T., Protective Groups in Organic Synthesis 10-86 (John Wiley &Sons 1981). The deprotection of the compound of general formula H inorder to produce the compound of general formula I′ is carried out underselective conditions maintaining the integrity of the R₂₃ radical, forexample, by treatment under acid conditions (for example bytrifluoroacetic acid). The selective conditions for the protection anddeprotection of functional groups are known to a person skilled in theart (Greene. T., Protective Groups in Organic Synthesis 10-86 (JohnWiley & Sons 1981)). The treatment of compound of general formula I′with a functionalized alkylating agent in order to produce a β-hydroxyester of general formula J can be carried out using a lithium enolate ora zinc derivative of a carboxylic ester in an anhydrous aprotic solvent,for example, tetrahydrofuran. The protective group R₂₃ of the compoundof general formula J is cleaved in order to produce a compound ofgeneral formula K under deprotection conditions known to a personskilled in the art. For example, when R₂₃ is a benzyl group, analcoholic solution of the compound of general formula J with a palladiumcatalyst added to it can be subjected to a hydrogen atmosphere under apressure of 0.5 to 10 Bar. The cyclization of the compound of generalformula K thus obtained can be carried out under acid conditions (forexample by treatment with trifluoroacetic acid, or hydrochloric gasdissolved in an anhydrous solvent such as dichloromethane or dioxan) inorder to produce a P-hydroxylactonic ring with seven members such as inthe compound of general formula L. The compounds of general formula Lcan be converted into pyridones of general formula M, for example, bytreatment with warm hydrochloric acid, or by treatment withtrimethylsilyl iodide. The 2-halo-3-quinoline methanols of generalformula N can be obtained starting from the acetanilides of generalformula P

[0794] in which R₂, R₃ and R₄ have the meaning indicated in the generalformulae of compounds I and II. In the processes below, the R₂, R₃ andR₄ groups can be protected if necessary according to standard protectionmethods (Greene. T., Protective Groups in Organic Synthesis 10-86 (JohnWiley & Sons 1981)).

[0795] The compounds of formula N can therefore be obtained according tothe following process: the said anilines of formula P are N-acetylatedby treatment with an acetylating agent such as, for example, aceticanhydride. The acetanilides thus obtained are treated at a temperaturecomprised between 50° C. and 1 00° C., preferably approximately 75° C.,with a reagent known to a person skilled in the art under the nameVilsmeyer's reagent (obtained by the action of phosphoryl oxychloride onNN-dimethylformamide at a temperature comprised between 0° C. and 10°C.) in order to produce the corresponding2-chloro-3-quinolinecarbaldehyde (for example, refer to Meth-Cohn et al.J. Chem. Soc., Perkin Trans. I p.1520 (1981); Meth-Cohn et al. J. Chem.Soc., Perkin Trans. I p.2509 (1981); and Nakasimhan et al. J. Am. Chem.Soc., 112 p.4431 (1990)). The chlorine in position 2 of the2-chloro-3-quinolinecarbaldehydes can be substituted by iodine orbromine by heating the product in an inert solvent such as acetonitrilein the presence of an iodine or bromine salt (for example sodium iodideor tetrabutylammonium bromide). A trace of acid such as concentratedhydrochloric acid may be necessary to catalyze this conversion. The2-halo-3-quinolinecarbaldehydes are easily reduced to the corresponding2-halo-3-quinolinemethanols of general formula N, under standardconditions known to a person skilled in the art such as treatment in analcoholic solvent (for example methanol) with sodium borohydride at atemperature comprised between 0° C. and 40° C.

[0796] The compounds of formula N can also be obtained according to thefollowing process: the anilines of general formula P as defined aboveare acylated by reaction with a nitrile (such as chloroacetonitrile orpropionitrile) in the presence of boron trichloride and another Lewisacid such as aluminium trichloride, titanium tetrachloride ordiethylaluminium chloride in an aprotic solvent or a mixture of aproticsolvents, followed by hydrolysis (cf. Sugasawa T. et al. J. Am. Chem.Soc. 100 p.4842 (1978)). The intermediate thus obtained is then treatedwith ethylmalonyl chloride in an aprotic solvent such as acetonitrile inthe presence of a base such as triethylamine, then treated with analkaline alcohol, for example, sodium methylate in methanol, in order toproduce an ethyl 2-hydroxy-3-quinolinecarboxylate substituted inposition 4. This is converted into ethyl 2-chloro-3-quinolinecarboxylateby treatment with phosphoryl oxychloride. When position 4 of thequinoline carries a chloromethyl group, a nucleophile substitution canbe carried out by treatment with a secondary amine such as, for example,dimethylamine, N-methylpiperazine, morpholine or piperidine. The ethyl2-chloro-3-quinolinecarboxylate is then reduced with diisobutylaluminiumhydride in an aprotic solvent such as dichloromethane in order toproduce the 2-chloro-3-quinolinemethanol of general formula N. Analoguesof intermediate compounds of general formula N have been described inthe literature and in particular in the PCT Application 95/05427.

[0797] The invention also offers, as a new industrial product, acompound of general formula M_(X) represented below:

[0798] wherein R is a lower alkyl group, and preferably ethyl.

[0799] This product can be used for the manufacture of medicaments.

[0800] The compound of formula M_(X) is synthesized according to a newprocess which is part of the invention and includes the followingsuccessive stages:

[0801] the racemic t-butyl ester represented below

[0802] (for its preparation, refer in particular to the PatentApplication WO 97/00876) is treated with trifluoroacetic acid for 18hours at ambient temperate in order to produce the correspondingcarboxylic acid;

[0803] then the quinidine salt of the acid obtained previously is heatedin isopropyl alcohol at a temperature greater than 30° C., andpreferably at about 50° C., before leaving the reaction medium to cooldown to ambient temperature, so that the salt of one of the enantiomersof the above-mentioned acid crystallized while the salt of the otherenantiomer, the anion of which is represented below, remains in solution

[0804] the solution in isopropyl alcohol of the salt of the enantiomerwhich has not crystallized is concentrated and treated with hydrochloricacid and agitated, producing the compound of general formula A_(X)represented below

[0805] the compound of general formula A_(X) is then put in contact withpalladium on damp carbon, then ammonium formate is added to the mixturein order to produce the debenzylated product of general formula B_(X)represented below

[0806] then the compound of general formula B_(X) is cyclized by theaction of dicyclohexylcarbodiimide in order to obtain the lactoniccompound of general formula C_(X) represented below

[0807] finally, the —OCH₃ group of the lactonic compound of generalformula C_(X) is converted into carbonyl, by the action of sodium iodideand trimethylsilyl chloride, in order to obtain a compound of generalformula M_(X) represented below.

[0808] For the process described above, the reaction leading from thecompound of general formula A_(X) to the compound of general formulaB_(X) will preferably take place in methanol, and preferably by heatingthe reaction medium to about 40° C. after the addition of the ammoniumformate. The cyclization of the compound of general formula B_(X) inorder to produce the compound C_(X) can be carried out in THF,preferably at a temperature of about 50° C., while the reaction willpreferably be carried out at ambient temperatue with acetonitrile assolvent in the reaction leading from the compound of general formulaC_(X) to the compound of general formula M_(X).

[0809] In the particular case where R represents an ethyl group, thecompound of formula M_(X) is synthesized according to the processconstituted by the following successive stages:

[0810] the racemic t-butyl ester represented below

[0811] (for its preparation, refer in particular to the PatentApplication WO 97/00876) is treated with trifluoroacetic acid for 18hours at ambient temperatue in order to produce the correspondingcarboxylic acid;

[0812] the quinidine salt of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid isheated in isopropyl alcohol at a temperature higher than 30° C., andpreferably at about 50° C., before leaving the reaction medium to cooldown to ambient temperatue, so that the salt of the (+) enantiomer of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acidcrystallizes whilst the salt of the (−) isomer the anion of which isrepresented below, remains in solution

[0813] the solution in isopropyl alcohol of the salt of the (−)enantiomer of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid isconcentrated and treated with hydrochloric acid and agitated, producingthe compound of formula A_(X)′ represented below

[0814] the compound A_(X)′ is then put in contact with palladium on dampcarbon, the ammonium formate is added to the mixture in order to producethe debenzylated product B_(X)′ represented below

[0815] then the compound of formula B_(X)′ is cyclized by the action ofdicyclohexylcarbodiimide in order to obtain the lactonic compound offormula C_(X)′ represented below

[0816] finally, the —OCH₃ group of the lactonic compound of formulaC_(X)′ is converted into carbonyl, by the action of sodium iodide andtrimethylsilyl chloride, in order to obtain(+)-5-ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pyridin-3,9-dione(or (+)-EHHOPD) represented below.

[0817] A subject of the invention is also, as new industrial productsand in particular as new industrial products intended for thepreparation of the products of general formula (B1) and (B2); theproducts of general formulae I′, M and M_(X) as described above.

[0818] The compounds of general formula (I_(A)) can be prepared in thefollowing manner:

[0819] the compound of formula M_(Y)

[0820] in which R₃₁ has the meaning indicated above, is coupled with acompound of formula N_(Y)

[0821] in which R₃₂, R₃₃, R₃₄, R₃₅ and R₃₆ have the meaning indicatedabove, to produce the compound of formula

[0822] in which R₃₂, R₃₃, R₃₄, R₃₅ and R₃₆ have the meaning indicatedabove.

[0823] compound O_(Y) is then cyclized to produce the compound offormula (I).

[0824] The formation of compounds O_(Y) starting from the compounds ofgeneral formulae M_(Y) and N_(Y) is carried out by a treatment known toa person skilled in the art under the name of Mitsunobu's reaction(refer to Mitsunobu, O. et al. Synthesis, p.1 (1981)). The hydroxylfunction of compound N_(Y) is displaced by a nucleophile such ascompound M_(Y) or a deprotonated derivative of the latter, by atreatment with a phosphine, for example triphenylphosphine, and anazodicarboxylate derivative, for example diethyl or diisopropylazodicarboxylate, in an aprotic solvent such as, for example,tetrahydrofuran or N,N-dimethylformamide. The cyclization of compoundsO_(Y) to produce the compounds of formula (I) is preferably carried outin the presence of a palladium catalyst (for example palladiumdiacetate) under basic conditions (provided for example by an alkalineacetate optionally combined with a phase transfer agent, such as, forexample, tetrabutylammonium bromide), in an aprotic solvent such asacetonitrile or N,N-dimethylformamide, at a temperature comprisedbetween 50° C. and 120° C. (R. Grigg et al., Tetrahedron 46, page 4003(1990)).

[0825] The invention also offers, as a new industrial product, acompound of general formula M_(Y) as defined previously. Preferably, R₃₁represents an ethyl radical. This product M_(Y) can be used for themanufacture of medicaments.

[0826] The compound of formula M_(Y) is prepared according to a newprocess which is part of the invention and includes the followingsuccessive stages:

[0827] a racemic ester represented below

[0828] in which R₃₁ has the meaning indicated above, R is a lower alkyland Z a protective group of the alcohol function (for its preparation,see in particular the Patent Application WO 97/00876) is converted tothe corresponding carboxylic acid;

[0829] this compound is then subjected to an operation which separatesthe enantiomers, known to the person skilled in the art under the nameof resolution (cf Jacques, et al., “Enantiomers, Racemates andResolution”, 2nd edition, Wiley, New-York, 1991), and which allows anenantiomerically enriched compound of general formula

[0830] to be obtained, in which R₃₁ and Z have the meaning indicatedabove;

[0831] the alcohol function of the compound of general formula A_(Y) isthen deprotected to produce the product of general formula

[0832] in which R₃₁ has the meaning indicated above,

[0833] the compound of general formula B_(Y) is cyclized in order toobtain the compound of general formula

[0834] in which R₃₁ has the meaning indicated above,

[0835] finally, the methoxy group of the compound of general formulaC_(Y) is converted to carbonyl in order to obtain a compound of generalformula

[0836] in which R₃₁ has the meaning indicated above.

[0837] In the particular case where R₃₁ represents an ethyl group, Rrepresents a tert-butyl and Z represents a benzyl group, the compound offormula M_(Y) is synthesized according to the process constituted by thefollowing successive stages:

[0838] the racemic t-butyl ester represented below (for its preparation,refer in particular to the Patent Application WO 97/00876)

[0839] is treated with trifluoroacetic acid for 18 hours at ambienttemperature to produce the corresponding carboxylic acid;

[0840] the quinidine salt of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid isheated at a temperature greater than 30° C., and preferablyapproximately 50° C. in isopropyl alcohol, before the reaction medium isallowed to cool down to ambient temperature so that the (+) enantiomersalt of 3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoicacid crystallizes whilst the (−) isomer salt, the anion of which isrepresented below, remains in solution

[0841] the solution in isopropyl alcohol of the (−) enantiomer salt of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid isconcentrated and treated with hydrochloric acid to produce the compoundof formula

[0842] compound A_(Y)′ is then put in contact with palladium in thepresence of a hydrogen source to produce the debenzylated product offormula B_(Y)′

[0843] the compound of formula B_(Y)′ is then cyclized in order toobtain the compound of formula C_(Y)′

[0844] finally, the methoxy group of the compound of formula C_(Y)′ isconverted to carbonyl is converted in order to obtain(+)-5-ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pyridin-3,9-dione (or (+)-EHHOPD) represented below.

[0845] For the process described above, the reaction leading from thecompound of formula A_(Y)′ to the compound of formula B_(Y)′ preferablytakes place in methanol, and preferably by heating the reaction mediumto about 40° C. after the addition of ammonium formate. The cyclizationof the compound of formula B_(Y)′ to produce compound C_(Y)′ can becarried out in THF, preferably at a temperature of about 50° C., whilethe reaction will preferably be carried out at ambient temperature withacetonitrile as solvent in the reaction leading from the compound offormula C′ to (+)-EHHOPD.

[0846] The compounds of formula (I_(A)) in which at least one of theradicals R₃₂, R₃₃, R₃₄ or R₃₅ represent a sulfonate, can be obtainedaccording to a process characterized in that the corresponding hydroxycompound is treated in an anhydrous aprotic solvent with a sulfonylingagent in presence of a base. The aprotic solvent may be dichloromethaneor N,N-dimethylfomamide, the sulfonyling agent methanesulfonylechloride, triflic anhydride, N-phenyltriflimide or p-toluene sulfonylchloride, and the base triethylamine, pyridine or sodium hydride.

[0847] The compounds of formula N_(Y), in which and R₃₆ is a hydrogenatom and R₃₂, R₃₃, R₃₄ and R₃₅ have the meaning indicated above, can beobtained from anilines of formula

[0848] in which R₂, R₃, R₄ and R₅ have the meaning indicated above,according to the following process: an aniline of formula P_(Y) isN-acetylated by treatment with an acetylating agent such as, forexample, acetic anhydride. The acetanilide thus obtained is treated at atemperature comprised between 50° C. and 100° C., preferably about 75°C., with a reagent known to a person skilled in the art under the nameVilsmeyer's reagent (obtained by the action of phosphoryl oxychloride onN,N-dimethylformamide at a temperature comprised between 0° C. and 10°C.) to produce the corresponding 2-chloro-3-quinolinecarbaldehyde (forexample, refer to Meth-Cohn et al. J. Chem. Soc., Perkin Trans. I p.1520 (1981); Meth-Cohn et al. J. Chem. Soc., Perkin Trans. I p. 2509(1981); and Nakasimhan et al. J. Am. Chem. Soc., 112 p. 4431 (1990)).This intermediate is easily reduced to the correspondingquinolylmethanol of formula N_(Y), under standard conditions known to aperson skilled in the art such as treatment in an alcoholic solvent (forexample methanol) with sodium borohydride at a temperature comprisedbetween 0° C. and 40° C.

[0849] The compounds of formula N_(Y) in which R₃₂, R₃₃, R₃₄, R₃₅ andR₃₆ have the meaning indicated above, can also be obtained fromcarboxylated quinolones of formula

[0850] in which R₃₂, R₃₃, R₃₄, R₃₅ and R₃₆ have the meaning indicatedabove, according to the following process: a quinolone of formula Q_(Y)is chlorinated to produce the corresponding chloroquinoline, thecarboxylated function of which is reduced to produce the compound ofgeneral formula N_(Y). The chlorination can be carried out with achlorophosphine oxide such as phosphorus oxychloride orchlorodiphenylphosphine oxide, pure or in the presence of an inertaprotic cosolvent such as toluene or chloroform, at a temperaturecomprised between 50° C. and 120° C. The chlorination is preferablycarried out with an excess of phosphorus oxychloride at 80° C. Thereduction can be carried out with an aluminium hydride in an aproticsolvent such as diethyl ether, tert-butylmethyl oxide, tetrahydrofuran,dichloromethane, chloroform, trichloroethane or toluene, at atemperature comprised between 0° C. and 50° C. The reduction ispreferably carried out with diisobutylaluminium hydride indichloromethane at ambient temperature.

[0851] The compounds of formula Q_(Y) in which and R₃₆ is a hydrogenatom and R₃₂, R₃₃, R₃₄ and R₃₅ have the meaning indicated above, can beobtained from anthranilic acids of formula

[0852] in which R₃₆ is a hydrogen atom and R₃₂, R₃₃, R₃₄ and R₃₅ havethe meaning indicated above, according to the following process: an acidof formula R_(Y) is reduced to produce the corresponding benzyl alcohol.The alcohol function of the intermediate thus obtained is protectedselectively in order to leave the amine function intact. The resultinganiline is acylated with a derivative of malonic acid. The previouslyprotected alcohol function is deprotected, then oxidized to produce thecorresponding carbonyl function, and the intermediate thus obtained issubjected to an intermolecular process according to a reaction known toa person skilled in the art under the name of Knovenagel's condensation,to produce carboxylated quinolones of formula Q_(Y), in which R₃₆ is ahydrogen atom and R₃₂, R₃₃, R₃₄ and R₃₅ have the meaning indicatedabove. The reduction of the acid to alcohol can be carried out by ametallic hydride in an inert aprotic solvent at a temperature comprisedbetween 0° C. and 50° C., and preferably by a mixed hydride of lithiumand aluminium in tetrahydrofuran at ambient temperature. The protectionof the intermediate benzyl alcohol can be carried out according to thegeneral methods known to the person skilled in the art (Greene T, etal., “Protective groups in Organic Synthesis”, 2nd edition, Wiley,New-York, 1991) or also with a silyl chloride in the presence of a base,in an aprotic solvent at a temperature comprised between 0° C. and 50°C., and preferably by tert-butyldiphenylsilyl chloride in the presenceof imidazole, in dimethylformamide at ambient temperature. Acylation canbe carried out with a malonic derivative such as ethylmalonyl chlorideor methyl malonate in the presence of a base such as triethylamine or4-dimethylaminopyridine in an aprotic solvent such as acetonitrile,tetrahydrofuran or toluene at a temperature comprised between 0° C. and110° C., and preferably with ethylmalonyl chloride in acetonitrile atambient temperature in the presence of triethylamine. Deprotection canbe carried out according to the protective group of the benzyl alcoholpreviously chosen (Greene, T.) and in the case of silylated ether by afluoride ion source such as cesium or potassium fluoride in the presenceof a phase transfer agent, or also tetrabutylammonium fluoride in anaprotic solvent such as tetrahydrofuran at a temperature comprisedbetween 0° C. and 50° C. and preferably at ambient temperature. Theoxidation can be carried out in the presence of chromium (VI) saltscarrying pyridyl ligands, by Swern's reagent, or also bypyridine-sulphur trioxide complex in dimethyl sulphoxide in the presenceof triethylamine, and preferably by pyridinium dichromate indichloromethane at ambient temperature. Knoevenagel's intermolecularcondensation can be carried out spontaneously or in solution in thepresence of a base, and preferably in dichloromethane in the presence oftriethylamine at ambient temperature.

[0853] The compounds of formula Q_(Y), in which R₃₂, R₃₃, R₃₄, R₃₅ andR₃₆ have the meaning indicated above, can be obtained from aminoketonesof formula

[0854] in which R₃₂, R₃₃, R₃₄, R₃₅ and R₃₆ have the meaning indicatedabove, according to the following process: an aminoketone S_(y) isacylated with a derivative of malonic acid and the intermediate thusobtained is subjected to an intermolecular process according to areaction known to a person skilled in the art under the name ofKnovenagel's condensation to produce carboxylated quinolones of formulaQ_(Y). Acylation can be carried out with a malonic derivative such asethylmalonyl chloride or methyl malonate in the presence of a base suchas triethylamine or 4-dimethylamino-pyridine in an aprotic solvent suchas acetonitrile, tetrahydrofuran or toluene at a temperature comprisedbetween 0° C. and 110° C., and preferably with ethylmalonyl chloride inacetonitrile at ambient temperature in the presence of triethylamine.Knovenagel's intermolecular condensation can be carried outspontaneously or in solution in the presence of a base, and preferablyin acetonitrile in the presence of sodium ethylate at ambienttemperature.

[0855] The aminoketones of formula S_(Y), in which R₃₂, R₃₃, R₃₄, R₃₅and R₃₆ have the meaning indicated above, can be obtained fromortho-aminated benzonitriles of formula

[0856] in which R₃₂, R₃₃, R₃₄ and R₃₅ have the meaning indicated above,by treatment with a Grignard's reagent of formula R₃₆—MgX, where X is ahalogen and R₃₆ has the meaning above according to methods known to theperson skilled in the art.

[0857] The aminoketones of formula S_(Y), in which R₃₆ is an arylradical and R₃₂, R₃₃, R₃₄ and R₃₅ have the meaning indicated above, canbe obtained from anthranilic acids of formula R_(Y) described above, bytreatment with benzoyl chloride under reflux to produce a benzoxazonewhich can be converted in the presence of Grignard's reagent of formulaR₃₆—MgX, where X is a halogen and R₃₆ is an aryl radical to thecorresponding ortho-aminated benzophenone, which can be debenzoylated byreagents such as, for example, hydrogen bromide in solution in water orin glacial acetic acid.

[0858] The aminoketones of formula S_(Y), in which R₃₂, R₃₃, R₃₄, R₃₅and R36 have the meaning indicated above, can be obtained from anilinesof formula P_(Y) in which R₃₂, R₃₃, R₃₄ and R₃₅ have the meaningindicated above, according to the following process: the nitrogen atomof an aniline of formula P_(Y) is acylated with an agent conferring anortho-directive character in the aryl metallation reaction, and thecompound thus obtained is metalated, then treated with an aldehyde offormula R₃₆—CHO in which R₃₆ has the meaning above. The process is thencompleted by oxidation of the alcoholic intermediate thus obtained, thenby release of the nitrogenous function to produce an aminoketone offormula S_(Y). For this process, passage to the ortho-directive functioncan be obtained by treating an aniline P_(Y) with a “bocant” agent andpreferably by di-tert-butyl dicarbonate in an aprotic solvent such astetrahydrofuran, dioxane or dimethoxyethane at reflux temperature. Themetallation can be obtained by treatment with a lithiated reagent suchas tert-butyllithium, sec-butyllithium, mesityllithium, or, in thepresence of tetramethyl-ethylenediamine, n-butyllithium, and preferablyn-butyllithium in the presence of tetramethyl-ethylenediamine, in anaprotic solvent such as tetrahydrofuran, dioxane or dimethoxyethane, ata temperature comprised between −80° C. and 0° C. Oxidation can becarried out in the presence of chromium (VI) salts carrying pyridylligands, by Swern's reagent, or also by the pyridine-sulphur trioxidecomplex in dimethylsulphoxide in the presence of triethylamine, andpreferably by pyridinium dichromate in dichloromethane under reflux. Thenitrogenous function can be obtained by treatment in acid medium, andpreferably by trifluoroacetic acid in dichloromethane at ambienttemperature.

[0859] Analogues of intermediate compounds of type N_(Y) have beendescribed previously and in particular in the PCT Application WO95/05427.

[0860] The compounds of formula (III)

[0861] in which

[0862] R₃₁ represents a lower alkyl radical;

[0863] R₃₂, R₃₃, R₃₄ and R₃₅ represent, independently, H, a halogen atomor —OSO₂R₄₀;

[0864] R₃₆ represents a linear or branched alkyl radical containing 1 to12 carbon atoms optionnally substituted by one or more halo radicalsindentical or different, lower hydroxy alkyl, lower alkoxy lower alkyl,lower cycloalkyl alkyl, —(CH₂)_(m)SiR₃₇R₃₈R₃₉ radical, or lower arylalkyl radical substituted or non substituted on the aryl group, thesubstituents being identical or different and selected from: a loweralkyl, a hydroxy group, halo, amino, lower alkyl amino, di(loweralkyl)amino, CF₃ or OCF₃;

[0865] R₃₇, R₃₈ and R₃₉ represent, independently, H or a lower alkylradical;

[0866] R₁₀ represents a lower alkyl radical optionnally substituted byone or more halo radicals identical or different, or an aryl optionnallysusbtituted by one or more lower alkyl radicals identical or different;

[0867] m is an integer comprised between 0 and 6;

[0868] can also be obtained by a new process, characterized in that acompound of formula

[0869] in which R₃₁, R₃₂, R₃₃, R₃₄ and R₃₅ have the meaning indicatedabove, is treated in a strongly acid medium in the presence of an iron(II) salt and a precursor of the free radical R₃₆*, by a solutioncontaining hydroxide or alkoxide radicals.

[0870] Although the prior art mentions the use of a similar reaction forthe analogues of camptothecines containing an α-hydroxylactone (Sawada,S., et al., Chem Pharm. Bull., (1991), vol. 39, p. 2574); PCTApplication WO 98/35940), its use for the analogues of camptothecinessuch as the compounds of formula (IV) containing a β-hydroxylactone, hasnot been foreseen and is unexpected, because in strongly acid medium, aternary and benzylic hydroxyl function, in position β with regard to acarboxylic function, is generally eliminated to produce thecorresponding olefine (Nagasawa, et al. Heterocycles 1989, vol. 28, p.703 ; Kimura, H. et al., Chem. Pharm. Bull. 1982, vol. 30, p. 552;Fujita, T. et al., J. Appl Chem Biotechnol. 1982, vol. 32, p. 421;Miller, R. E., et al., J. Org. Chem. 1950, vol. 15, p. 89; Fieser, L.F., et al., J. Am. Chem. Soc. 1948, vol. 70, p. 3209).

[0871] In the process above, the strongly acid medium can be provided byacids such as aqueous or non-aqueous trifluoroacetic acid or sulphuricacid and preferably aqueous sulphuric acid, the iron (III) salt willpreferably be heptahydrated iron (III) sulphate, the free radicalprecursor will be an aldehyde of formula R₃₆—CHO in which R₃₆ representsan alkyl radical containing 1 to 12 carbon atoms optionnallysubstituted, lower hydroxy alkyl, lower alkoxy lower alkyl, lowercycloalkyl alkyl, —(CH₂)_(m)SiR₃₇R₃₈R₃₉ radical, or lower aryl alkylradical substituted or non substituted on the aryl group. The solutioncontaining hydroxide or alkoxide radicals may be provided by hydrogenperoxide or tert-butyl hydroperoxide, and preferably by hydrogenperoxide at 30 volumes.

[0872] Certain compounds of the invention can be prepared in the form ofpharmaceutically acceptable salts according to the usual methods.Acceptable salts include, by way of example and in a non-limitativefashion, the addition salts with inorganic acids such as hydrochloride,sulphate, phosphate, diphosphate, hydrobromide, and nitrate or withorganic acids such as acetate, maleate, fumarate, tartrate, succinate,citrate, lactate, methane sulphonate, p-toluenesulphonate, pamoate,salicylate, oxalate and stearate. The salts formed from bases such assodium or potassium hydroxide also form part of the field of applicationof the present invention, when they are useable. For other examples ofpharmaceutically acceptable salts one can refer to “PharmaceuticalSalts”, J. Pharm. Sci. 66:1 (1977).

[0873] The compounds of the present invention possess usefulpharmacological properties. Thus the compounds of the present inventionhave an inhibitory effect on topoisomerase I and/or II and ananti-tumoral activity. The state of the art suggests that the compoundsaccording to the invention have an anti-parasitic and/or anti-viralactivity. The compounds according to the present invention can also beused in different therapeutic applications.

[0874] An illustration of the pharmacological properties of thecompounds according to the invention will be found hereafter in theexperimental part.

[0875] The compounds can inhibit topoisomerase, for example of type Iand/or II, in a patient, for example a mammal such as man, byadministration to this patient of a therapeutically effective quantityof a compound of formula (A1) or a compound of formula (A2).

[0876] The compounds according to the invention also have ananti-tumoral activity. They can be used for the treatment of tumors, forexample tumors expressing a topoisomerase, in a patient byadministration to the latter of a therapeutically effective quantity ofa compound of formula (A1) or a compound of formula (A2). Examples oftumors or cancers include cancers of the oesophagus, the stomach, theintestines, the rectum, the oral cavity, the pharynx, the larynx, thelung, the colon, the breast, the cervix uteri, the corpus endometrium,the ovaries, the prostate, the testicles, the bladder, the kidneys, theliver, the pancreas, the bone, the connective tissues, the skin, theeyes, the brain and the central nervous system, as well as cancer of thethyroid, leukemia, Hodgkin's disease, lymphomas other than those relatedto Hodgkin, multiple myelomas and others.

[0877] They can also be used for the treatment of parasitic infectionsby inhibition of the hemoflagellates (for example in trypanosomia orleishmania infections) or by inhibition of the plasmodia (such as forexample in malaria), but also the treatment of viral infections anddiseases.

[0878] These properties make the products of formula (A1) and (A2)suitable for pharmaceutical use. A subject of the present application isalso, as medicaments, the products of formula (A1) and (A2) as definedabove as well as the addition salts with pharmaceutically acceptablemineral or organic acids of said products of formula (A1) and (A2), aswell as the pharmaceutical compositions containing at least one of themedicaments as defined above as active ingredient.

[0879] An object of the invention is therefore methods of treatment ofdiseases related with topoisomerase I and/or topoisomerase II disorders,and especially cancer, viral and parasitic diseases, comprising theadministration of a therapeutically efficient dose of a camptothecinanalog, said camptothecin analog being characterized in that it featuresa β-hydroxy lactone instead of the α-hydroxy lactone of naturalcamptothecin.

[0880] Another object of the invention is methods of treatment ofdiseases related with topoisomerase I and/or topoisomerase II disorders,and especially cancer, viral and parasitic diseases, comprising theadministration of a therapeutically efficient dose of a compound ofgeneral formula (A1) or a compound of general formula (A2).

[0881] In particular, an object of the invention is methods of treatmentas previously described comprising the administration of any of theβ-hydroxy lactone camptothecin analogues disclosed in the presentapplication, especially those of general formula (HCPT) and thosedescribed in the examples.

[0882] Thus the invention relates to a method of treating cancer inwarm-blooded animals comprising administering to warm-blooded animals inneed thereof a camptothecin analog characterized in that said analog isa [A,B,C,D,E] pentacyclic compound, the cycles [A,B,C,D]

[0883] comprising any substitution on the various sites available forsubstitution(s), and the [E] cycle being a 7-ring member β-hydroxylactone ring of the formula

[0884] wherein R₁ is selected from the group consisting of alkyl of 1 to6 carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms, haloalkyl of1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms andalkylthioalkyl of 2 to 12 carbon atoms, R_(p) is hydrogen or an easilycleavable group, R₁₈ and R₁₉ are individually selected from the groupconsisting of hydrogen, halogen, OH and alkyl and alkoxy of 1 to 6carbon atoms and its non-toxic, pharmaceutically acceptable salts.

[0885] The invention preferably relates to a method of treating canceras defined above, the cycles [A,B,C,D] comprising any substitution onthe sites 8, 9, 10, 11, 12 or 13, and more preferably on the sites 8, 9,10, 11 or 12.

[0886] More preferably, the invention relates to a method of treatingcancer as defined above, the cycles [A,B,C,D] comprising anysubstitution on the sites 9, 10, 11 or 12.

[0887] The invention relates also to a method of treating cancer inwarm-blooded animals comprising administering to warm-blooded animals inneed thereof a camptothecin having 5 rings with a 7-ring memberβ-hydroxy lactone ring of the formula

[0888] wherein R₁ is selected from the group consisting of alkyl of 1 to6 carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms, haloalkyl of1 to 6 carbon atoms, alkoxy alkyl of 2 to 12 carbon atoms andalkylthioalkyl of 2 to 12 carbon atoms, R_(p) is hydrogen or an easilycleavable group, R₁₈ and R₁₉ are individually selected from the groupconsisting of hydrogen, halogen, OH and alkyl and alkoxy of 1 to 6carbon atoms and its non-toxic pharmaceutically acceptable salts.

[0889] The invention preferably relates to one of the methods oftreating cancer as defined above, characterized in that cancer isselected from the group consisting of leukemia, colon cancer, lungcancer, prostate cancer, breast cancer, melanoma, ovarian cancer andgastric cancer, and more preferably leukemia, colon cancer, lung cancer,prostate cancer and breast cancer.

[0890] The invention preferably relates also to one of the methods asdefined above, characterized in that R₁₈ and R₁₉ are hydrogen.

[0891] The invention preferably relates also to one of the methods asdefined above, characterized in that R_(p) is hydrogen.

[0892] The invention preferably relates also to one of the methods asdefined above, characterized in that R₁ is ethyl.

[0893] More preferably, the invention relates to one of the methods asdefined above, characterized in that camptothecin analog is selectedfrom:

[0894](5R)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0895](5R)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4:6,7]indolizino[1,2-b]quinolin-12-yl-methyl]-4-methyl-bexahydropyridiumchloride;

[0896](5R)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;

[0897](5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;or its pharmaceutically acceptable salts thereof.

[0898] The invention also relates to pharmaceutical compositionscontaining a compound according to the invention or an addition saltwith a pharmaceutically acceptable acid of it, in combination with apharmaceutically acceptable support according to the chosenadministration method (for example oral, intravenous, intraperitoneal,intramuscular, trans-dermic or sub-cutaneous). The pharmaceuticalcomposition (for example therapeutic) can be in the form of a solid,liquid, liposome or lipidic micella.

[0899] The pharmaceutical composition can be in solid form, for example,powders, pills, granules, tablets, liposomes, gelatin capsules orsuppositories. The pill, tablet or gelatin capsule can be covered in asubstance which is capable of protecting the composition from the actionof gastric acid or enzymes in the stomach of the subject for asufficient period of time to allow this composition to pass in anon-digested form into the small intestine of the latter. The compoundcan also be administered locally, for example, at the same location asthe tumor. The compound can also be administered according to asustained release process (for example a sustained release compositionor an infusion pump). The appropriate solid supports can be, forexample, calcium phosphate, magnesium stearate, magnesium carbonate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.The pharmaceutical compositions containing a compound according to theinvention can also be presented in liquid form such as, for example,solutions, emulsions, suspensions or a sustained release formulation.The appropriate liquid supports can be, for example, water, organicsolvents such as glycerol or glycols such as polyethylene glycol,similarly their mixtures, in varied proportions, in water.

[0900] A subject of the invention is also the use of the products offormula (A1) or (A2) as defined above for the preparation of medicamentsintended to inhibit topoisomerase and more particularly topoisomerase oftype I or type II, medicaments intended for the treatment of tumors,medicaments intended for the treatment of parasitic infections, as wellas medicaments intended for the treatment of viral diseases.

[0901] Of course, the products of general formula (B1), (B2), (I_(A)),(HCPT), (I), (II), (I)_(op) and (II)_(op) can be used according to theinvention analogously to the products of formula (A1) or (A2).

[0902] The dose of a compound according to the present inventionenvisaged for the treatment of the diseases or disorders mentionedabove, varies according to the administration method, the age and bodyweight of the subject as well as the state of the latter and it will bedecided definitively by the attending doctor or vet. Such a quantitydetermined by the attending doctor or vet is called here “effectivetherapeutic quantity”.

[0903] Unless defined in another manner, all the technical andscientific terms used here have the same meaning as that commonlyunderstood by an ordinary specialist in the field to which the inventionbelongs. Similarly, all publications, Patent Applications, all Patentsand all other references mentioned here are incorporated by way ofreference.

[0904] The following examples are presented to illustrate the aboveprocedures and must in no case be considered as a limit to the scope ofthe invention.

EXPERIMENTAL PART Example 1 tert-butyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

[0905] 1.a.4-ethyl-3,4-dihydroxy-1,3,4,12-tetrahydro-14H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-14-one

[0906] Sodium borohydride (14 g, 370 mmol) is added by portions to asuspension of (S)-(+)-camptothecin (14 g, 40 mmol, which can be obtainedfrom different commercial sources such as Aldrich Chemical Co.(Milwaukee, Wis.)), in methanol (750 ml) and the resultant mixture isheated gently to 55° C. in order to obtain a limpid solution which isthen agitated for 16 hours at ambient temperature. The solvent is thenevaporated off under reduced pressure, the residue is taken up in water(250 ml), neutralized by the addition of acetic acid (21 ml) and left atrest for 2 hours at 4° C. The resultant suspension is filtered andwashed successively with cold water, acetone and diethyl ether, whichallows the sought product to be obtained, after drying under reducedpressure, in the form of a white solid m.p. 280° C.

[0907] 1.b.(9-oxo-7-propionyl-9,11-dihydroindolizino[1,2-b]quinolin-8-yl)methylformate

[0908] A solution of sodium metaperiodate (14 g, 65 mmol) in water (140ml) is added dropwise to a suspension of4-ethyl-3,4-dihydroxy-1,3,4,12-tetrahydro-14H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-14-one(13.4 g, 38 mmol) in glacial acetic acid (720 ml) and the resultantsolution is agitated for one hour at ambient temperature. The reactionmixture is then poured into an ice/water mixture (650 ml) and theresultant suspension is then agitated for half an hour then filtered andwashed successively with water, isopropyl alcohol and diethyl ether,which allows the sought product (11.5 g) to be obtained, after dryingunder reduced pressure, in the form of a pale yellow solid m.p. >200° C.(d).

[0909] 1.c. tert-butyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

[0910] A suspension of zinc (6.5 g, 100 mmol) stirred with a magneticstirrer in anhydrous diethyl ether (50 ml) under argon, is activated bythe dropwise addition of chlorotrimethylsilane (0.75 ml, 5.7 mmol).Stirring is continued for 15 minutes at ambient temperature then thereaction medium is heated to reflux. The heating bath is then removedand tert-butyl bromoacetate (15 ml, 100 mmol) is added dropwise at arate which ensures reflux is maintained. The external heating is putback and heating is continued for one hour. The resultant etherealsolution of Reformatsky's reagent is left to cool down to ambienttemperature then transferred using a cannula into a suspension of(9-oxo-7-propionyl-9,11-dihydroindolizino[1,2-b]quinolin-8-yl)methylformate (1.6 g, 4.7 mmol) in anhydrous tetrahydrofuran (40 ml) underargon. The reaction mixture is agitated under reflux for one hour, thenleft to cool down to ambient temperature and the reaction is stopped bythe addition of saturated ammonium chloride (100 ml) and extraction iscarried out with chloroform (3×100 ml). The combined chloroformicextracts are dried over sodium sulphate, evaporated and the residue ispurified by chromatography on a silica gel column (1-2% MeOH/CH₂Cl₂),which allows 0.64 g (31%) of sought product to be obtained in the formof a pale yellow solid, m.p. 146-149° C.

[0911] NMR-1H (CDCl₃): 0.93 (t, 3H); 1.37 (s, 9H); 1.99 (m, 2H); 2.97(dd, 2H); 3.5 (se, 1H); 5.10 (s, 2H); 5.24 (s, 2H); 7.40 (s, 1H); 7.59(t, 1H); 7.83 (t, 1H); 7.90 (d, 1H); 8.20 (d, 1H); 8.34 (s, 1H).

[0912] NMR-C13 (CDCl₃): 8.18; 27.90; 34.59; 45.34; 49.91; 58.55; 77.39;82.42; 100.52; 127.67; 127.97; 128.10; 128.64; 129.44; 129.79; 130.42;130.99; 142.86; 148.69; 152.75; 155.16; 162.38; 172.24.

[0913] IR (KBr): 764; 1016; 1157; 1580; 151; 1726.

Example 2 ethyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

[0914] A suspension of zinc (500 mg, 7.64 mmol) and(9-oxo-7-propionyl-9,11-dihydroindolizino[1,2-b]quinolin-8-yl)methylformate (400 mg, 1.15 mmol) in anhydrous tetrahydrofuran (20 ml)containing 10 mg of hydroquinone is heated to reflux under argon. Theheating bath is removed and the exothermic reaction is initiated by theaddition of a drop of ethyl bromoacetate and a small crystal of iodine.Reflux is maintained by the dropwise addition of ethyl bromoacetate (500μl, 4.48 mmol) then the reaction mixture is again heated to reflux forone hour. After cooling down to ambient temperature, the reaction isstopped by the addition of saturated ammonium chloride (10 ml) andmethanol (30 ml). The resultant mixture is agitated for 5 minutes thenfiltered and evaporated. The residue is dissolved in dichloromethane (30ml), washed with water and dried over sodium sulphate. Then the solventis eliminated and purification using column chromatography is carriedout (SiO₂, CH₂Cl₂/MeOH 98/2), which produces 230 mg (49%) of soughtcompound in the form of a yellow solid, m.p. 157-161° C.

[0915] NMR-¹H (CDCl₃): 0.93 (t, 3H); 1.20 (t, 3H); 2.02 (m, 2H); 3.07(dd, 2H); 4.11 (q, 2H); 4.9 (se, 1H); 5.08 (s, 2H); 5.23 (s, 2H); 7.45(s,1H); 7.62 (t, 1H); 7.80 (t,1H); 7.90 (d, 1H); 8.22 (d, 1H); 8.36(s,1H).

[0916] NMR-C¹³ (CDCl₃): 8.09; 14.01; 34.67; 44.85; 49.94; 58.31; 61.09;77.21; 100.78; 127.78; 127.96; 128.11; 128.72; 129.16; 129.65; 130.60;131.32; 142.76; 148.28; 152.55; 155.09; 162.22; 172.59.

[0917] IR(KBr): 766; 1009; 1184; 1582; 1647; 1750.

Example 35-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[0918] tert-butyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate(1.45 g, 3.32 mmol) is dissolved in anhydrous dichloromethane (25 ml)and treated with a saturated solution of hydrogen chloride indichloromethane (100 ml). The resultant mixture is maintained at −20° C.for 16 hours.

[0919] The precipitate is filtered, washed with methanol and dried underreduced pressure, which allows 662 mg (55%) of sought product to beobtained in the form of a yellow solid, m.p. >300° C.

[0920] NMR-¹H (DMSO): 0.90 (t, 3H); 1.20 (q, 2H); 3.27 (dd, 2H); 5.29(s, 2H); 5.49 (dd, 2H); 7.42 (s, 1H); 7.73 (t, 1H); 7.90 (t, 1H); 8.16(t, 2H); 8.71 (s, 1H).

[0921] NMR-C¹³ (DMSO): 8.45; 36.48; 42.54; 50.68; 61.44; 73.34; 99.78;122.71; 127.83; 128.15; 128.75; 129.08; 130.07; 130.61; 131.81; 144.66;148.04; 152.80; 155.91; 159.26; 172,08.

[0922] IR (KBr): 761; 1127; 1204; 1285; 1580; 1653; 1757.

Example 43-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoicacid

[0923] An aqueous solution of potassium hydroxide (0.1N, 30 ml) is added5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(500 mg, 1.38 mmol) and the resultant suspension is agitated at ambienttemperature for 16 hours, which produces a virtually limpid solutionwhich is filtered. The filtrate is acidified to pH 3.5 with 1Nhydrochloric acid, and the yellow precipitate is recovered byfiltration, washed with water and with acetone then dried under reducedpressure. 415 mg (79%) of sought compound is obtained in the form of amonohydrate, m.p. 165-167° C.

[0924] NMR-¹H (DMSO): 0.82 (t, 3H); 2.10 (m, 2H); 2.83 (d, 2H); 3.12 (d,2H); 3.25 (se, 1H); 4.81 (s, 2H); 5.26 (s, 2H); 5.76 (se, 1H); 7.38 (s,1H); 7.71 (t, 1H); 7.84 (t, 1H); 8.10 (d, 1H); 8.18 (d, 1H); 8.34 (s,1H); 12.15 (se, 1H).

[0925] NMR-C¹³ (DMSO): 8.16; 34.80; 46.71; 50.36; 55.73; 76.53; 100.17;127.50; 128.00; 128.26; 128.69; 129.06; 130.01; 130.45; 131.63; 142.57;148.09; 153.19; 156.07; 161.22; 172.27.

[0926] IR(KBr): 1020; 1188; 1413; 1586; 1651; 1694.

Example 5 methyl3-hydroxy-3-[8-(methoxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

[0927]5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(180 mg, 0.5 mmol), in suspension in methanol (50 ml) is treated with 6Ndry hydrogen chloride in methanol (0.5 ml) and maintained under refluxuntil complete dissolution (4 hours). The volatile compounds areevaporated off and the residue is dissolved in dichloromethane (50 ml),washed with dilute sodium hydroxide (0.05 N, 15 ml) and brine (15 ml).The organic fraction is dried over sodium sulphate and evaporated. Thesolid residue is purified by chromatography in a silica gel column (MeOHat 3%/CH₂CL₂) and the purified product is taken up in diethyl ether,filtered and dried, which produces 120 mg (58%) of sought compound inthe form of a pale yellow solid, m.p. 163-166° C.

[0928] NMR-¹H (CDCl₃): 0.93 (t, 3H); 1.2 (m, 2H); 3.05 (dd, 2H); 3.49(s, 3H); 3.62 (s, 3H); 4.93 (s, 2H); 5.22 (d, 2H); 5.52 (s, 1H); 7.21(s, 1H); 7.62 (t, 1H); 7.81 (t, 1H); 7.91 (d, 1H); 8.22 (d, 1H); 8.36(s, 1H).

[0929] NMR-C¹³ (CDCl₃): 7.74; 35,54; 46.82; 50.15; 51.67; 58.10; 65.33;78.03; 100.17; 125.57; 127.70; 128.04; 128.10; 128.35; 129.53; 130.39;130.94; 143.87; 148.75; 152.94; 157.83; 161.74; 171.35.

[0930] IR (KBr): 1207; 1595; 2655; 1709.

Example 6 ethyl2,2-difluoro-3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate

[0931] Approximately half of a total quantity of ethylbromodifluoroacetate (1.8 ml, 14 mmol),(9-oxo-7-propionyl-9,11-dihydroindolizino[1,2-b]quinolin-8-yl)methylformate (2,0 g, 5.75 mmol, as obtained in Stage 1.b.) in suspension inanhydrous THF (10 ml), are added dropwise under argon to a suspension ofzinc (1.25 g, 17.2 mmol) in anhydrous THF under reflux (40 ml) then theremaining part of the ethyl bromodifluoroacetate is added. The reactionmixture is maintained under reflux for another half an hour. Aftercooling down to ambient temperature, the reaction is stopped by theaddition of saturated ammonium chloride (20 ml) and the reaction mixtureis extracted with dichloromethane (3×20 ml). The combined organicextracts are dried and concentrated. The residue is taken up in diethylether (10 ml), filtered and purified by column chromatography (SiO₂,CH₂Cl₂/MeOH:98/2), which produces 664 mg (26%) of product in the form ofa yellow solid, m.p. 208-209° C.

[0932] NMR-¹H (CDCl₃): 0.91 (t, 3H); 1.38 (t, 3H); 2.32 (m, 2H); 4.8(se, 1H); 4.38 (q, 2H); 5.09 (d, 2H); 5.13 (dd, 2H); 7.42 (s, 1H); 7.55(t, 1H); 7.72 (t, 1H); 7.79 (d, 1H); 8.08 (d, 1H); 8.22 (s, 1H)

[0933] NMR-C¹³ (CDCl₃): 6.97; 13.93; 28.63; 50.18; 56.27; 63.15; 77.20;81.96 (t); 101.27; 116.40(t); 127.67; 127.77; 127.97; 128.31; 129.26;130.33; 130.94; 131.23; 143.16; 148.34; 150.20; 151.91; 161.21; 163.21(t).

[0934] IR(KBr): 1124; 1308; 1591; 1647; 1748.

Example 7 ethyl3-hydroxy-3-(8-methyl-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl)pentanoate

[0935] A suspension of zinc (1.25 g, 19.1 mmol),8-methyl-7-propionylindolizino [1,2-b]quinoline-9-(11H)-one (500 mg,1.43 mmol, as obtained by Kingsburry, W. D., Tetrahedron Left. 29:6847(1988)) and silver acetate (250 mg, 1.50 mmol) in anhydroustetrahydrofuran (10 ml) is agitated at ambient temperature under anargon atmosphere. After 10 minutes, the reaction mixture is activated bythe dropwise addition of a molar solution of chlorodiethylaluminium (10ml, 10 mmol), then ethyl bromoacetate (1.25 ml, 11.3 mmol) is addeddropwise and the resultant mixture is left to react for another 5 hours.The reaction is stopped by the successive addition of ethyl alcohol (10ml) and a saturated solution of potassium and sodium tartrate (10 ml).The resultant mixture is agitated for another hour, filtered andconcentrated under reduced pressure. The residue is taken up indichloromethane (30 ml), washed with water, dried, concentrated andpurified by column chromatography (SiO₂, CH₂Cl₂/MeOH:98/2), whichproduces 93 mg (15%) of desired product in the form of a pale yellowsolid, m.p. 185-188° C.

[0936] NMR-¹H (CDCl₃): 0.91 (t, 3H); 1.17 (t, 3H); 1.99 (m, 2H); 2.49(s, 3H); 3.10 (dd, 2H); 4.11 (q, 2H); 4.6 (se, 1H); 5.25 (s, 2H); 7.65(t, 1H); 7.67 (s, 1H); 7.80 (t, 1H); 7.90 (d, 1H); 8.22 (d, 1H); 8.34(s, 1H).

[0937] NMR-C¹³ (CDCl₃): 8.02; 13.99; 14.72; 33.14; 43.97; 50.02; 61.0;76.54; 101.90; 127.65; 127.84; 128.08; 128.81; 128.88; 130.74; 131.59;131.65; 140.33; 147.64; 152.96; 153.61; 162.11; 172.91.

[0938] IR(KBr): 762; 1192; 1576; 1653; 1740.

Example 8 tert-butyl3-{8-[(acetyloxy)methyl]-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl}-3-hydroxypentanoate

[0939] Acetic anhydride (70 μl, 0.7 mmol) is added dropwise to asolution of tert-butyl3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate(200 mg, 0.46 mmol) and triethylamine (140 μl, 1 mmol) indichloromethane (5 ml) and the resultant mixture is agitated at ambienttemperature for 21 hours. The volatile components are evaporated off andthe residue is purified by chromatography on a silica gel column (1-2%MeOH/CH₂Cl₂), which produces 152 mg of sought compound in the form of ayellow solid, m.p. 195-196° C.

[0940] NMR-¹H (CDCl₃): 0.88 (t, 3H); 1.32 (s, 9H); 1.93 (m, 2H); 2.07(s, 3H); 2.97 (dd, 2H); 4.8 (se, 1H); 5.28 (s, 2H); 5.59 (dd, 2H); 7.39(s, 1H); 7.63 (t, 1H); 7.78 (t, 1H); 7.90 (d, 1H); 8.23 (d, 1H); 8.34(s, 1H).

[0941] NMR-C¹³ (CDCl₃): 8.02; 21.06; 27.91; 35.05; 45.58; 50.16; 59.23;77.52; 82.26; 100.59; 124.21; 127.91; 128.10; 128.14; 128.97; 129.18;130.68; 131.46; 142.85; 148.29; 152.43; 158.49; 161.83; 171.13; 171.90.

Example 95,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[0942] This compound is prepared in a similar manner to Example 1,except that in Stage 1.a., 7-ethyl camptothecin (Sawada andcollaborators, Chem. Pharm. Bull. 39:2574 (1991)) is used instead ofcamptothecin. The sought compound is obtained in the form of a vividyellow solid, m.p. >270° C.

[0943] NMR-¹H (DMSO): 0.92 (t, 3H); 1.39 (t, 3H); 1.93 (q, 2H); 3.08 (d,2H); 3.25 (q, 2H); 3.51 (d, 2H); 5.32 (s, 2H); 5.52 (dd, 2H); 7.42 (s,1H); 7.76 (t, 1H); 7.89 (t, 1H); 8.18 (d, 1H); 8.32 (d, 1H).

[0944] NMR-C¹³ (DMSO): 8.46; 14.15; 22.42; 36.50; 42.54; 49.95; 61.45;73.35; 99.68; 122.61; 124.27; 126.76; 127.70; 128.27; 129.92; 130.18;145.17; 145.82; 148.57; 152.15; 155.89; 159.26; 172.08.

Example 103-[12-ethyl-8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]-3-hydroxypentanoicacid

[0945] This compound is prepared in a similar manner to Example4,5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dioneis used instead of the5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione.It is presented in the form of a slightly dirty white solid, m.p.238-239° C.

[0946] NMR-¹H (DMSO): 0.82 (t, 3H); 1.35 (t, 3H); 2.01 (m, 2H); 2.85 (d,2H); 3.18 (d, 2H); 3.22 (q, 2H); 4.81 (s, 2H); 5.00 (se, 1H); 5.24 (s,2H); 5.78 (se, 1H); 7.38 (s, 1H); 7.77 (t, 1H); 7.86 (t, 1H); 8.18 (d,1H); 8.28 (d, 1H); 12.10 (se, 1H).

[0947] NMR-C¹³ (DMSO): 8.12; 14.15; 22.41; 34.78; 46.74; 49.65; 55.71;76.51; 100.04; 124.22; 126.63; 127.48; 128.12; 128.21; 129.94; 130.02;143.10; 145.59; 148.69; 152.62; 156.03; 161.22; 172.22.

Example 118-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione

[0948] 11.a. 4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine (F)

[0949] The water is distilled in an azeotropic manner (overnight) with aDean Stark apparatus from a mixture of 2-chloro-4-propionylpyridine (10g, 59 mmol) obtained as in Lamattina, J. L. J. Heterocyclic Chem. 20, p.553 (1983), ethylene glycol (20 ml) and p-toluenesulphonic acid (250 mg)in toluene (150 ml). The solvent is then eliminated under reducedpressure, the acid is neutralized with saturated aqueous sodiumbicarbonate (100 ml) and the product is extracted with ether. Thecombined ethereal extracts are washed with brine, dried over sodiumsulphate and evaporated, which produces 13.3 g (96%) of crude productprotected by the carbonyl group which is heated to reflux with 3equivalents of sodium methoxide in acetonitrile until the end of thereaction (checked by thin layer chromatography: SiO₂, tert-butyl methyloxide/hexane (TBMO/HX) 50/50). The acetonitrile solution is thenfiltered and evaporated. The residue is taken up in ether, washed withwater and with brine, dried over sodium sulphate and evaporated, whichproduces a brown oil which is distilled (70-75° C., 0.04 mbar); 10.7 g(overall yield 81%) of product (F) is collected in the form of a clearoil.

[0950] 11.b.[4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-pyridinyl]methanol (G)

[0951] tert-butyllithium (1.7 M in pentane, 100 ml, 170 mmol) is addeddropwise using a cannula to a solution of bromomesitylene (13 ml, 85mmol) in anhydrous tetrahydrofuran (300 ml) at −78° C. and under argon.The resultant white precipitate is agitated at −78° C. for one hour then4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine (10 g, 44.8 mmol) isadded and the reaction mixture is agitated for 15 minutes at −78° C.,for one hour at 0° C. and for one hour at ambient temperature. Afteragain cooling down to −78° C., anhydrous N,N-dimethylformamide (100mmol) is added and the reaction mixture is left to heat up to ambienttemperature then agitated for 16 hours, after which analysis by thinlayer chromatography (SiO₂, TBMO/HX: 50/50) reveals the completeconsumption of the starting product. The reaction is stopped withsaturated ammonium chloride and the reaction mixture is extracted withdiethyl ether (200 ml, 50 ml, 50 ml). The combined extracts are driedover sodium sulphate and evaporated, which produces a yellow oil whichis purified by column chromatography (SiO₂, TBMO/HX: 0/100 to 5/95 toelute the mestylene derivatives then 20/80 to 50/50 to elute theproduct) in order to obtain the intermediate aldehyde (7 g). Thealdehyde is dissolved in methanol (100 ml) and treated with sodiumborohydride (5 g, 132 mmol) and the resultant mixture is agitated untilcomplete consumption of the intermediate aldehyde (approximately 1 hour)with analytical control by thin layer chromatography. The solvent isthen evaporated off, the residue is taken up in ether, washed with waterand with brine, dried and the solvent is evaporated off. Columnchromatography (SiO₂, TBMO/HX: 10/90 to 50/50) of the residue produces 7g (overall yield 62%) of product (G) in the form of a yellow oil.

[0952] 11.c.3-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine(H)

[0953] A solution of[4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-pyridinyl]methanol (7 g, 30mmol) and benzyl chloride (5 ml, 45 mmol) in anhydrous tetrahydrofuran(50 ml) is added dropwise to a suspension of sodium hydride (80% inmineral oil, 1.85 g, 61 mmol) in anhydrous tetrahydrofuran (100 ml) andthe reaction mixture is maintained under reflux for 16 hours. Thereaction mixture is then left to cool down to ambient temperature, thereaction is stopped with water (50 ml) and the reaction mixture isconcentrated under reduced pressure. The residue is dissolved in diethylether (150 ml) and washed with water and with brine, dried andevaporated. Purification by column chromatography (SiO₂, TBMO/HX: 5/95to 20/80) produces the product protected by the benzyl (H), 9 g, (87%)in the form of a limpid oil.

[0954] 11.d. 1-{3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl}-1-propanone(I′)

[0955]3-[(Benzyloxy)methyl]-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine (9g, 27 mmol) is treated with trifluoroacetic acid (10 ml) and water (5ml) at a bath temperature of 120° C. for 3 hours. The reaction mixtureis concentrated under reduced pressure and the residual traces of acidsare neutralized by the addition of saturated aqueous sodium bicarbonate.Extraction is carried out with ether followed by column chromatography(SiO₂, TBMO/HX: 10/90) which produces 5.5 g (70%) of product (I).

[0956] 11.e. tert-butyl3-{3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl}-3-hydroxy pentanoate (J)

[0957] tert-butyl bromoacetate (13 ml, 80 mmol) is added dropwise to azinc suspension (5.3 g, 80 mmol activated with 6N HCl over 10 seconds,then washed successively with water until a neutral pH is achieved, withacetone and with diethyl ether) in anhydrous tetrahydrofuran (60 ml)under reflux. The reaction medium is maintained under reflux for another10 minutes after the addition is terminated. Then, a solution of1-{3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl}-1-propanone (5.8 g, 20mmol) in anhydrous tetrahydrofuran (20 ml) is added and the reactionmixture is agitated under reflux for another hour. The reaction isstopped at 0° C. with saturated aqueous ammonium chloride (100 ml) andthe reaction mixture is extracted with diethyl ether. The combinedextracts are dried over sodium sulphate and evaporated, which produces ayellow oil which is purified by column chromatography (SiO₂, TBMO/HX:5/95 to 10/90) in order to obtain the tert-butyl ester (J) (7 g, 95%) inthe form of a limpid liquid.

[0958] 11.f. tert-butyl3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate (K)

[0959] tert-Butyl3-{3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl}-3-hydroxypentanoate (1g, 2.5 mmol) is subjected to hydrogenolysis at atmospheric pressure andat ambient temperature using 5% palladium on carbon as catalyst (50 mg)and absolute ethanol as solvent (10 ml). Once the reaction hasterminated (6 hours), the catalyst is separated by filtration and thesolvent is evaporated off, which leaves 0.7 g (90%) of product (K) of asufficient purity for a subsequent synthetic use.

[0960] 11.g.5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one(L)

[0961] tert-butyl3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate (8.8 g,28 mmol) is treated with trifluoroacetic acid (30 ml) for 3 hours atambient temperature. The volatile components are evaporated off and theresidue is purified by column chromatography (SiO₂, CH₂Cl₂/MeOH: 100/0to 98/2), which produces a limpid oil which, after treatment withtoluene, produces 5.9 g of product (L) (89%) in the form of whitecrystals, m.p. 97-98° C.

[0962] 11.h.5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione (M)

[0963]5-Ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one(0.5 g, 2.1 mmol) is heated under reflux for 9 hours in 1N hydrochloricacid (20 ml). The reaction mixture is concentrated under reducedpressure and the residue is again dried by the addition and evaporationof toluene twice, then left overnight under reduced pressure in thepresence of phosphorus pentoxide. The resultant oil is dissolved inanhydrous acetonitrile (5 ml) and agitated under argon for 24 hours. Theprecipitate is filtered out and dried, which produces 0.23 g (49%) of awhite solid (M), m.p. 118-119° C.

[0964] 11.i.(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methanol (N)

[0965] The procedures described by Meth-Cohn et al., J. Chem. Soc.Perkin Trans. I, p. 1520 (1981); Meth-Cohn, J. Chem. Soc. Perkin Trans.I, p. 2509 (1981); and Nakasimhan et al J. Am. Chem. Soc. 112, p. 4431(1990), are used. N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide (22 g,113 mmol) is added to the Vilsmeyer reagent obtained by the dropwiseaddition of phosphoryl oxychloride (71 ml, 0.77 mol) to anhydrousdimethylformamide (23 ml, 0.28 mol), cooled down with a water/ice bathand agitated again for 0.5 hours under an argon atmosphere. Theresultant mixture is heated at 75° C. for 16 hours. After cooling downto ambient temperature, the reaction mixture is added to a mixture ofice and water (300 ml) and extracted with dichloromethane (5×200 ml).The combined organic extracts are dried over sodium sulphate, filteredand concentrated. The solid residue is suspended in dichloromethane (20ml), filtered and dried under reduced pressure, which produces 10 g(35%) of 7-chloro-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbaldehydein the form of a yellow solid, m.p. 222-224° C. This intermediate istreated with sodium iodide (30 g, 0.2 mol) and concentrated hydrochloricacid (1.5 ml) in acetonitrile under reflux (150 ml) for 24 hours. Aftercooling down to ambient temperature, the solvent is eliminated underreduced pressure and the residue is taken up in aqueous tetrahydrofuranat 50% (200 ml), filtered, washed with tetrahydrofuran and dried underreduced pressure, which produces 12 g of7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbaldehyde in theform of a yellow solid, m.p. 155-157° C. The above intermediate istreated with sodium borohydride (2 g, 52 mmol) in methanol (200 ml) atambient temperature for 0.5 hours. The solvent is eliminated underreduced pressure and the residue is taken up in water and filtered. Theresultant solid is dried under reduced pressure in the presence ofphosphorus pentoxide, which produces 11 g of(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methanol in the formof a yellow solid, m.p. 178-180° C.

[0966] 11.j.5-ethyl-5-hydroxy-8-[(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methyl]-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione(O)

[0967] Diethyl azodicarboxylate (570 l, 3.6 mmol) is added dropwise over5 minutes to a solution of5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione(400 mg, 1.79 mmol), the compound obtained in the preceding Stage, 11.i.(770 mg, 2.23 mmol) and triphenylphosphine (934 mg, 3.58 mmol) in amixture of anhydrous THF/DMSO (8/1 v/v, 45 ml) and the resultant mixtureis agitated under argon at ambient temperature for 16 hours. Thereaction mixture is then concentrated under reduced pressure and theresidue is dissolved in chloroform (100 ml). The resultant solution iswashed with brine (4×50 ml), dried over sodium sulphate and evaporated.The residue is purified by column chromatography (SiO₂, CH₂Cl₂/MeOH:99/1 to 98/2), which produces 650 mg (66%) of product (O) in the form ofa white solid, m.p. 165-167° C.

[0968] 11.k.8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione

[0969] 5-ethyl-5-hydroxy-8-[(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methyl]-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione(600 mg, 1.1 mmol), tetrabutyl-ammonium bromide (352 mg, 1.1 mmol),sodium acetate (359 mg, 4.4 mmol) and palladium II acetate (98 mg, 0.43mmol) are dissolved in anhydrous acetonitrile (40 ml) and heated at 90°C. under argon for 16 hours. After cooling down to ambient temperature,a white precipitate is separated from the reddish solution. Thisprecipitate is filtered out and dried under reduced pressure. The crudeproduct is suspended in water, filtered and dried under reduced pressureover phosphorus pentoxide which produces 250 mg of sought compound inthe form of a clear yellow solid, m.p. >250° C.

[0970] NMR-¹H (DMSO): 0.91 (t, 3H); 1.87 (m, 2H); 3.08 (d, 1H); 3.51 (d,1H); 4.45 (s, 4H); 5.19 (s, 2H); 5.47 (dd, 2H); 6.02 (se, 1H); 7.33 (s,1H); 7.54 (s, 1H); 7.5 (s, 1H); 8.43 (s, 1H).

[0971] NMR-C¹³ (DMSO): 8.43; 36.47; 42.54; 50.52; 61.43; 64.43 (2C);73.31; 99.07; 112.27; 113.14; 122.00; 124.24; 128.18; 129.74; 144.59;145.01; 145.33; 147.63; 150.88; 155.88; 159.23; 172.07.

Example 1210-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[0972] 12.a. [6-(benzyloxy)-2-iodo-3-quinolinyl]methanol

[0973] This compound is prepared in a similar manner to that indicatedin Stage 11.i. of Example 11, but by using 4N-[4-(benzyloxy)phenyl]acetamide instead ofN-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide. Purification bychromatography on a silica gel column and the use of dichloromethane aseluant are necessary in order to isolate the intermediate6-(benzyloxy)-2-chloro-3-quinolinecarbaldehyde, m.p. 180-182° C. (yield8%) with sufficient purity. Then, the halogen exchange produces6-(benzyloxy)-2-iodo-3-quinolinecarbaldehyde, m.p. 155-157° C. and asubsequent reduction with sodium borohydride produces[6-(benzyloxy)-2-iodo-3-quinolinyl]methanol, m.p. 147-149° C.

[0974] 12.b.8-{[6-(benzyloxy)-2-iodo-3-quinolinyl]methyl}-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione

[0975] This compound is prepared in a similar manner to that indicatedin Stage 11.j. of Example 11, but by using[6-(benzyloxy)-2-iodo-3-quinolinyl]methanol instead of(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methanol. Thiscompound is presented in the form of a white solid m.p. 197-199° C.

[0976] 12.c.10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[0977] This compound is prepared in a similar manner to that indicatedin Stage 11.k. of Example 11, but by using8-{[6-(benzyloxy)-2-iodo-3-quinolinyl]methyl}-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dioneinstead of5-ethyl-5-hydroxy-8-[(7-iodo-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl)methyl]-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione.The sought compound is presented in the form of a clear yellow solidm.p. >250° C.

[0978] NMR-¹H (DMSO): 0.90 (t, 3H); 1.85 (m, 2H); 3.08 (d, 1H); 3.50 (d,1H); 5.25 (s, 2H); 5.30 (s, 2H); 5.50 (dd, 2H); 6.05 (s, 1H); 7.30-7.70(m, 8H); 8.10 (d, 1H); 8.55 (s, 1H).

[0979] NMR-C¹³ (DMSO): 8.43; 36.48; 38.28; 50.65; 61.42; 70.00; 73.32;99.05; 107.71; 122.05; 123.42; 128.18; 128.26; 128.70; 129.40; 130.19;130.48; 130.63; 136.65; 144.18; 144.90; 150.53; 155.91; 157.31; 159.24;172.06.

Example 133-[2-(benzyloxy)-8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]-3-hydroxypentanoicacid (E)

[0980] This compound is prepared in a similar manner to that indicatedin Example 4, but by using10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dioneinstead of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione.It is presented in the form of a yellow solid, m.p. 171-173° C.

[0981] NMR-¹H (DMSO): 0.80 (t, 3H); 2.00 (m, 2H); 2.85 (d, 1H); 3.15 (d,1H); 4.80 (s, 2H); 5.25 (s, 2H); 5.30 (s, 2H); 5.75 (se, 1H); 7.30 (s,1H); 7.35-7.70 (m, 7H); 8.10 (d, 1H); 8.55 (s, 1H).

[0982] NMR-C¹³ (DMSO): 8.11; 34.75; 46.68; 50.35; 55.70; 69.97; 76.51;99.45; 107.78; 123.28; 127.64; 128.18 (2C); 128.26; 128.70 (2C); 129.33;130.17; 130.47; 130.57; 136.69; 142.79; 144.17; 150.93; 156.03; 157.19;161.20.

Example 145-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[0983]10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(370 mg, 0.79 mmol) is treated with hydrogen under atmospheric pressureand at ambient temperature using 10% palladium on carbon as catalyst (60mg) and trifluoroacetic acid as solvent (15 ml). Once the reaction isterminated (16 hours), dichloromethane (50 ml) and methanol (50 ml) areadded to the reaction mixture, the catalyst is filtered out and thevolatile components are evaporated off under reduced pressure whichallows the sought crude compound to be obtained containing traces oftrifluoroacetic acid. These traces are eliminated by co-distillationwith 1,4-dioxan. The product is obtained in the form of an orange solid,m.p. 150° C. (d), of a sufficient purity for a subsequent synthetic use.

[0984] NMR-¹H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 3.02 (d, 1H); 3.45 (d,1H); 5.19 (s, 2H); 5.37 (d, 1H); 5.50 (d, 1H); 5.98 (se, 1H); 7.26 (s,1H); 7.31 (s, 1H); 7.40 (d, 1H); 8.00 (d, 1H); 8.42 (s, 1H); 10.32 (s,1H).

[0985] NMR-C¹³ (DMSO): 8.47; 36.50; 42.61; 50.57; 61.46; 73.35; 98.84;109.02; 121.83; 123.18; 129.50; 129.85; 130.12; 130.80; 143.39; 145.10;149.69; 155.97; 156.82; 159.30; 172.11.

Example 1511-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dionehydrochloride

[0986] 15.a.11-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[0987] A suspension of5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(260 mg, 0,69 mmol) in acetic acid (15 ml) is treated with aqueousformaldehyde at 37% (500 μl) and aqueous dimethylamine at 40% (500 μl)and the resultant mixture is agitated at ambient temperature for 16hours. The reaction mixture is concentrated to dryness and the residueis purified by column chromatography (SiO₂, CH₂Cl₂/MeOH: 100/0 to 90/10)followed by crystallization from acetonitrile, which produces 102 mg ofsought compound.

[0988] 15.b.11-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dionehydrochloride

[0989] Dilute hydrochloric acid (1N) is added dropwise to a suspensionof 11-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione (102 mg) in water until complete dissolution. The wateris evaporated off under reduced pressure and the residue is suspended inacetonitrile (5 ml) and filtered, which produces 103 mg of the soughtsalt m.p. 248° C. (d).

[0990] NMR-¹H (DMSO): 0.88 (t, 3H); 1.85 (m, 2H); 2.84 (s, 6H); 3.08 (d,1H); 3.5 (d, 1H); 4.73 (s, 2H); 5.25 (s, 2H); 5.47 (dd, 2H); 7.33 (s,1H); 7.38 (s, 1H); 7.72 (d, 1H); 8.19 (d, 1H); 8.99 (s, 1H); 9.92 (se,1H); 11.45 (s, 1H).

[0991] NMR-C¹³ (DMSO): 8.46; 34.36; 42.44 (3C); 50.61 (2C); 61.42;73.35; 99.19; 108.63; 122.21; 122.36; 126.86; 129.13; 130.61; 133.09;143.53; 144.70; 149.76; 155.98; 157.17; 159.27; 172.06.

Example 165-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[0992] This compound is obtained from 3-fluoro-4-methoxyanilineaccording to the method illustrated in Stages 11i, 11j and 11k ofExample 11. Yellow solid, m.p. >250° C.

[0993] NMR-¹H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 3.08 (d, 1H); 3.49 (d,1H); 4.00 (s, 3H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.00 (s,1H); 7.32 (s, 1H); 7.72 (d, 1H); 7.91 (d, 1H); 8.58 (s, 1H).

[0994] NMR-C¹³ (DMSO): 8.43; 36.48; 42.51; 50.68; 56.60; 61.42; 73.29;99.25; 108.68; 113.52; 122.23; 126.33; 129.99; 130.30; 143.79; 144.70;148.42; 151.18; 153.19; 155.81; 159.20; 172.06.

[0995] IR (KBr): 1259; 1503; 1602; 1737.

Example 179-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[0996] This compound is obtained from 3-chloro-4-methylaniline accordingto the method illustrated in Stages 11i, 11j and 11k of Example 11.Yellow solid, m.p. >250° C.

[0997] NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 2.55 (s, 3H); 3.07 (d,1H); 3.45 (d, 1H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s,1H); 7.39 (s, 1H); 8.10 (s, 1H); 8.20 (s, 1H); 8.60 (s, 1H).

[0998] NMR-C¹³ (DMSO): 8.43; 20.20; 36.47; 42.49; 50.67; 61.41; 73.28;99.87; 122.82; 126.98; 127.99; 129.60; 130.53; 131.08; 135.64; 136.56;144.39; 147.11; 153.10; 155.85; 159.18; 172.03.

[0999] IR(KBr): 1208; 1479; 1606; 1656; 1724.

Example 185-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1000] This compound is obtained from 3,4-difluoroaniline according tothe method illustrated in Stages 11i, 11j and 11k of Example 11. Yellowsolid; m.p. >250° C.

[1001] NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.47 (d,1H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.39 (s,1H); 8.15 (q, 1H); 8.25 (q, 1H); 8.68 (s, 1H).

[1002] NMR-C¹³ (DMSO): 8.41; 36.45; 42.48; 50.68; 61.40; 73.25; 99.92;114.44; 115.42; 115.58; 122.96; 125.52; 130.56; 131.46; 144.21; 145.25;142.36; 153.41; 155.85; 159.15; 172.00.

[1003] IR(KBr): 1266; 1512; 1581; 1618; 1751.

Example 197-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione

[1004] This compound is obtained from 3,4-methylenedioxyanilineaccording to the method illustrated in Stages 11i, 11j and 11k ofExample 11. Cream solid; m.p. >250° C.

[1005] NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d,1H); 5.20 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.00 (s, 1H); 6.30 (s,2H); 7.30 (s, 1H); 7.49 (d, 2H); 8.45 (s, 1H).

[1006] NMR-C¹³ (DMSO): 8.43; 36.49; 42.56; 50.58; 61.42; 73.31; 98.87;102.75; 103.33; 104.92; 121.76; 125.74; 128.59; 130.33; 145.08; 146.69;148.78; 150.19; 151.49; 155.90; 159.24; 172.08.

[1007] IR (KBr): 1248; 1459; 1606; 1731.

Example 209-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1008] This compound is obtained from 3-chloro-4-methoxyanilineaccording to the method illustrated in Stages 11i, 11j and 11k ofExample 11. White solid; m.p. >250° C.

[1009] NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2); 3.07 (d, 1H); 3.45 (d,1H); 4.01 (s, 3H); 5.22 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.02 (s,1H); 7.31 (s, 1H); 7.68 (s, 1H); 8.20 (s, 1H); 8.55 (s, 1H).

[1010] NMR-C¹³ (DMSO): 8.22; 36.27; 42.30; 50.48; 56.69; 61.23; 73.08;99.16; 107.44; 122.16; 127.12; 128.12; 129.25; 130.02; 130.53; 143.29;144.37; 151.12; 153.29; 155.71; 158.98; 171.84.

[1011] IR (KBr): 1056; 1256; 1483; 1592; 1657; 1747.

Example 215-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1012] This compound is obtained from 4-methoxyaniline according to themethod illustrated in Stages 11.i., 11.j. and 11.k. of Example 11.Yellow solid; m.p. >250° C.

[1013] NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d,1H); 3.95 (s, 3H); 5.28 (s, 2H); 5.40 (d, 1H); 5.51 (d, 1H); 6.00 (s,1H); 7.38 (s, 1H); 7.51 (d, 2H); 8.07 (d, 1H); 8.55 (s, 1H).

[1014] NMR-C¹³ (DMSO): 8.45; 36.48; 42.51; 50.64; 55.92; 61.42; 73.33;99.01; 106.49; 122.02; 123.19; 129.59; 130.20; 130.43; 144.17; 144.94;150.40; 155.92; 158.31; 159.26; 172.07.

[1015] IR(KBr): 1251; 1604; 1655; 1735.

Example 229,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1016] This compound is obtained from 3,5-dichloroaniline according tothe method illustrated in Stages 11.i., 11.j. and 11.k. of Example 11.Yellow solid; m.p. >250° C.

[1017] NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d,1H); 5.30 (s, 2H); 5.41 (d, 1H); 5.55 (d, 1H); 6.08 (s, 1H); 7.41 (s,1H); 8.05 (s, 1H); 8.21 (s, 1H); 8.91 (s, 1H).

[1018] NMR-C¹³ (DMSO): 8.39; 36.45; 42.51; 51.03; 61.39; 73.25; 100.62;123.55; 124.63; 127.60; 128.08; 128.56; 132.06; 132.19; 134.53; 143.77;148.80; 154.88; 155.82; 159.13; 171.98.

[1019] IR (KBr): 1064; 1275; 1586; 1651; 1743.

Example 235-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1020] This compound is obtained from 3-fluoro-4-methylaniline accordingto the method illustrated in Stages 11.i., 11.j. and 11.k. of Example11. Yellow solid; m.p. >250° C.

[1021] NMR-¹H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 2.49 (s, 3H); 3.08 (d,1H); 3.49 (d, 1H); 5.21 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s,1H); 7.39 (s, 1H); 7.87 (d, 1H); 8.05 (d, 1H); 8.61 (s, 1H).

[1022] NMR-C¹³ (DMSO): 8.40; 15.14; 36.45; 42.52; 50.60; 61.41; 73.28;99.71; 112.00; 122.66; 125.38; 127.66; 129.59; 130.28; 144.49; 147.88;152.88; 155.85; 159.18; 162.25; 172.02.

[1023] IR(KBr): 1054; 1580; 1651; 1760.

Example 245-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1024] This compound is obtained from 4-fluoroaniline according to themethod illustrated in Stages 11.i., 11.j. and 11.k. of Example 11. Whitesolid; m.p. >250° C.

[1025] NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d,1H); 5.29 (s, 2H); 5.39 (d, 1H); 5.55 (d, 1H); 6.30 (s, 1H); 7.39 (s,1H); 7.80 (q, 1H); 7.99 (q, 1H); 8.23 (q, 1H);8.68 (s, 1H).

[1026] NMR-C¹³ (DMSO): 8.40; 36.46; 42.48; 50.66; 61.41; 73.31; 99.68;111.83; 122.75; 128.93; 130.93; 131.22; 131.93; 144.46; 145.27; 152.60;155.89; 159.21; 172.04.

[1027] IR (KBr): 1209; 1589; 1659; 1739.

Example 2510-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1028] This compound is obtained from 4-chloroaniline according to themethod illustrated in Stages 11.i., 11.j. and 11.k. of Example 11.Yellow solid. m.p. >250° C.

[1029] NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.47 (d,1H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.39 (s,1H); 7.89 (d, 1H); 8.19 (d, 1H); 8.29 (s, 1H); 8.67 (s, 1H).

[1030] NMR-C¹³ (DMSO): 8.40; 36.46; 42.47; 50.70; 61.42; 73.31; 100.00;122.96; 127.31; 127.42; 128.87; 131.11; 132.12; 144.34; 146.53; 153.38;155.88; 159.20; 172.04.

[1031] IR(KBr): 1069; 1483; 1606; 1741.

Example 269-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1032] This compound is obtained from 3-chloro-4-fluoroaniline accordingto the method illustrated in Stages 11.i., 11.j. and 11.k. of Example11. Yellow solid. m.p.>250° C.

[1033] NMR-¹H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d,1H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.40 (s,1H); 8.20 (d, 1H); 8.40 (d, 1H); 8.68 (s, 1H).

[1034] NMR-C¹³ (DMSO): 8.38; 36.47; 42.58; 50.71; 61.40; 73.26; 99.99;113.59; 123.09; 124.28; 127.74; 130.64; 131.31; 144.13; 145.08; 153.57;154.13; 155.84; 156.61; 159.14; 172.00.

[1035] IR(KBr): 1488; 1583; 1655; 1743.

Example 275-ethyl-5,10-dihydroxy-11-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1036] This compound is obtained from morpholine according to the methodillustrated in Example 15.a. White solid, m.p.>250° C.

[1037] NMR-¹H (DMSO): 0.85 (t, 3H); 1.87 (q, 2H); 2.53 (s, 4H); 3.03 (d,1H); 3.45 (d, 1H); 3.57 (s, 4H); 4.02 (s, 2H); 5.01 (s, 2H); 5.38 (d,1H); 5.52 (d, 1H); 6.0 (se, 1H); 7.30 (s, 1H); 7.42 (d, 1H); 7.95 (d,1H); 8.82 (s, 1H).

[1038] NMR-C¹³ (DMSO): 8.45; 3.49; 42.58; 53.04; 61.44; 66.33; 73.33;98.81; 113.78; 121.81; 122.74; 126.80; 129.05; 129.91; 143.72; 145.07;149.24; 155.06; 156.92; 159.28; 172.08.

[1039] IR(KBr): 1515; 1595; 1654; 1736.

Example 285,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1040] 28.a. 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone

[1041] (This product is obtained according to Sugasawa T; Toyoda T;Adachi M; Sasakura K, J Am. Chem. Soc., 100 (1978), p.4842-4852). Borontrichloride (1M in heptane, 156 ml, 156 mmol) is added dropwise, underan argon atmosphere at 0° C. to a solution of 3-fluoro-4-methoxy-aniline(20 g, 142 mmol) in anhydrous dichloromethane (200 ml). The pinksuspension thus obtained is maintained under agitation for 5 minutes,then propionitrile (33 ml, 420 mmol) is added dropwise followed byaluminium trichloride (20.8 g, 156 mmol) in small portions. The reactionmedium is heated under reflux for 3 hours, cooled down to 0° C.,hydrolyzed by cautiously adding 2N hydrochloric acid (100 ml), thenheated at reflux for 45 minutes. After cooling down to 0° C. aprecipitate is obtained which is filtered out, washed withdichloromethane, then taken up in water (300 ml). The aqueous phase isbasified to an alkaline pH, extracted with dichloromethane then ethylacetate. The organic phase is dried (MgSO₄) then evaporated to produce acrude product which is purified by column chromatography (SiO₂,AcOEt/Hpt: 1/99 to 20/80). 15.3 g of a yellow solid is obtained.

[1042] NMR-¹H (CDCl₃): 1.20 (t, 3H); 2.92 (q, 2H); 3.83 (s, 3H); 6.2 (s,2H); 6.40 (d, 2H); 7.32 (d, 2H).

[1043] IR(KBr): 857; 1148; 1240; 1561; 1583; 1662.

[1044]28.b. ethyl4-ethyl-7-fluoro-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate

[1045] A solution of ethylmalonyl chloride (12.9 ml, 100 mmol) inanhydrous acetonitrile (30 ml) is added dropwise, under argon and at 0°C. to a solution of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone(15.3 g, 77.5 mmol) and triethylamine (13.9 ml, 100 mmol) in anhydrousacetonitrile (110 ml). The reaction medium is left to return to ambienttemperature, a solution of sodium ethylate (obtained by 1.8 g, 78 mmolof sodium in 80 ml of ethanol) is cannulated dropwise and under argon,then the reaction medium is left under agitation for 12 hours at ambienttemperature. The reaction mixture is poured into ice-cooled water (100ml) and agitation is carried out for two hours, then the precipitate isfiltered out and washed with water, with ethanol and with ether. 19.4 gof a white solid is obtained.

[1046] NMR-¹H (DMSO): 1.25 (m, 6H); 2.78 (q, 2H); 3.92 (s, 3H); 4.30 (q,2H); 7.15 (d, 2H); 7.40 (d, 2H); 11.93 (s, 1H).

[1047] IR (KBr): 786; 1083; 1410; 1521; 1644; 1725.

[1048] 28.c. ethyl2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate

[1049] A suspension of ethyl4-ethyl-7-fluoro-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate(19.4 g, 0.066 mol) in phosphoryl chloride (243 ml) is heated at refluxfor 6 hours. The phosphoryl chloride is distilled off. The reactionmixture is decanted into ice-cooled water, then taken up indichloromethane to solubilize. The organic phase is washed with water,then with a saturated solution of sodium chloride. The organic phase isdried over magnesium sulphate and the solvent is evaporated off. Theresidue is suspended in ether and the non-converted starting product (4g) is filtered out. The filtrate is evaporated and the residue ispurified by column chromatography (SiO₂, AcOEt/Hpt: 5/95 to 20/80). 10.9g of a white solid is obtained.

[1050] NMR-¹H (DMSO): 1.30 (t, 3H); 1.39 (t, 3H); 3.08 (q, 2H); 4.09 (s,3H); 4.49 (q, 2H); 7.64 (d, 2H); 7.86 (d, 2H).

[1051] IR(KBr): 865; 1016; 1082; 1190; 1224; 1253; 1272; 1508; 1571;1732.

[1052] 28.d. (2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinyl)methanol

[1053] A solution of ethyl2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate (10.8 g, 35mmol) in anhydrous dichloromethane (200 ml) is treated dropwise atambient temperature under an inert atmosphere with diisobutylaluminiumhydride (1M in dichloromethane, 65 ml, 65 mmol), then heated at 40° C.for 4 hours. After cooling down to 0° C., a 20% aqueous solution ofRochelle salt (105 ml) and dichloromethane (200 ml) are added cautiouslyand the reaction mixture is maintained under agitation for 1 hour,followed by decanting and washing three times with water. The organicphase is dried over magnesium sulphate and the solvent is evaporatedoff. The residue is purified by column chromatography (SiO₂, AcOEt/Hpt:5/95 to 50/50). 6 g of a white solid is obtained.

[1054] NMR-¹H (DMSO): 1.28 (t, 3H); 3.25 (q, 2H); 4.04 (s, 3H); 4.77 (d,2H); 5.27 (t, 1H); 7.55 (d, 2H); 7.73 (d, 2H).

[1055] IR(KBr): 840; 864; 1023; 1232; 1267; 1317; 1444; 1511; 1569.

[1056] 28.e.5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1057] (2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinyl)methanol iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the proceduredescribed in Stage 11.k. A yellow solid is obtained, m.p.>275° C.

[1058] NMR-¹H (CF3COOD): 1.07 (m, 3H); 1.62 (m, 3H); 2.27 (m,2H); 3.44(d, 1H); 3.54 (m, 2H); 3.91 (d, 1H); 4.25 (s, 3H); 5.60 (d, 1H); 5.74(s, 2H); 5.98 (d, 1H); 7.85 (m, 1H); 8.16 (m, 1H); 8.31 (s, 1H).

[1059] NMR-C¹³ (CF3COOD): 9.03; 14.20; 26.68; 38.77; 43.98; 53.79;58.27; 64.73; 77.93; 106.85; 109.24; 110.15; 128.99; 129.20; 131.61;137.32; 141.23; 144.13; 154.79; 158.32; 160.25; 160.81; 179.30.

[1060] IR(KBr): 1013; 1068; 1265; 1466; 1514; 1601; 1655; 1748.

Example 295-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1061] The procedure described in Examples 28.b., 28.c. and 28.d. isapplied to 2-acetylaniline in order to produce(2-chloro-4-methyl-3-quinolinyl)methanol. The latter coupled to compound(M) as described in Stage 11.j. of Example 11. The resultant coupledproduct is cyclized according to the procedure of Stage 11.k. A yellowsolid is obtained, m.p.>260° C.

[1062] NMR ¹H (DMSO): 0.87 (t, 3H); 1.87 (q, 2H); 2.78 (s, 3H); 2.80 (d,1H); 3.55 (d, 1H); 5.27 (s, 2H); 5.42 (d, 1H); 5.52 (d, 1H); 6.04 (s,1H); 7.39 (s, 1H); 7.75 (t, 1H); 7.88 (t, 1H); 8.13 (d, 1H); 8.25 (d,1H).

[1063] NMR-C¹³ (DMSO): 8.23; 36.26; 42.36; 62.00; 73.11; 78.65; 79.13;79.25; 99.52; 122.36; 124.30; 127.67; 129.54; 129.55; 129.56; 140.11;145.06; 148.07; 152.00; 155.79; 159.09; 171.89.

[1064] IR (KBr): 1649; 1751; 3404.

Example 309-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,71indolizino[1,2-b]quinoline-3,15-dione

[1065] 30.a. 5-chloro-2-chloroacetyl-4-methoxyaniline

[1066] This product is obtained according to Sugasawa T; Toyoda T;Adachi M; Sasakura K, J Am. Chem. Soc., 100 (1978), p.4842-4852. A molarsolution of boron trichloride in hexane (164 ml, 164 mmol),chloroacetonitrile (11,4 ml, 180 mmol), and a molar solution ofdiethylaluminium chloride in hexane (164 ml, 164 mmol). are addeddropwise and successively under an inert atmosphere at 0° C. to asolution of 3-chloro-4-methoxyaniline (23,6 g, 150 mmol). The reactionmedium is heated under reflux for 1 hour, cooled down to 0° C.,hydrolyzed by cautiously adding 2N hydrochloric acid (90 ml), thenheating to reflux for 1 hour. The reaction medium is cooled down and aconcentrated soda solution is added until pH 14. Extraction is carriedout with ethyl acetate, the organic phase is washed with water, thenwith salt water. Followed by drying over magnesium sulphate, filteringand evaporating under reduced pressure. The residue is taken up inisopentane, followed by decanting, then the insoluble part is taken upin the minimum amount of isopropyl ether, isopentane is added in orderto precipitate the product, followed by filtering and drying undervacuum. 17.26 g of a brown solid is obtained.

[1067] NMR-¹H (CDCl₃): 3.82 (s, 3H); 4.60 (s, 2H); 6.11 (s, 2H); 6.78(s, 1H); 7.11 (s, 1H);

[1068] 30.b. ethyl7-chloro-4-(chloromethyl)-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate

[1069] A solution of ethylmalonyl chloride (17 ml, 131 mmol) is addeddropwise under argon and at 0° C. to a solution of5-chloro-2-chloroacetyl-4-methoxyaniline (17 g, 73 mmol) andtriethylamine (18,5 ml, 131 mmol) in anhydrous acetonitrile (310 ml).Agitation is carried out for 2 hours at ambient temperature, then asolution of sodium ethanolate in ethanol (obtained by 1.88 g, 80 mmol,of sodium in 90 ml of ethanol) is added dropwise at 0° C. . Agitation iscarried out for 12 hours at ambient temperature. 300 ml of water isadded, and agitation is again carried out for 20 minutes. Theprecipitate is filtered out; washed with water, with ethanol, and withethyl ether. After drying under vacuum 16.7 g of a yellowish solid isobtained.

[1070] NMR-¹H (DMSO): 1.31 (t, 3H); 3.95 (s, 3H); 4.36 (q, 2H); 4.95 (s,2H); 7.46 (s, 1H); 7.49 (s, 1H).

[1071] 30.c. ethyl2,7-dichloro-4-(chloromethyl)-6-methoxy-3-quinolinecarboxylate

[1072] A suspension of ethyl7-chloro-4-(chloromethyl)-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate(116.7 g, 50 mmol) in phosphoryl chloride (100 ml) is heated to refluxfor 6 hours. The phosphoryl chloride is distilled off. The residue istaken up in water and agitation is carried out for 30 min. Theprecipitate is filtered out and washed with water until neutrality. Theprecipitate is taken up in dichloromethane and with a saturated solutionof sodium chloride. After filtering through a bed of celite the filtrateis decanted. The organic phase is washed again with a saturated solutionof sodium chloride, followed by drying over magnesium sulphate,filtering and evaporating under reduced pressure. 15.88 g of a brown oilis obtained.

[1073] NMR-¹H (CDCl₃): 1.47 (t, 3H); 4.08 (t, 3H); 4.55 (q, 2H); 4.87(s, 2H); 7.35 (s,1H) 8.09 (s, 1H).

[1074] 30.d. ethyl2,7-dichloro-6-methoxy-4-[(4-methyl-1-piperazinyl)methyl]-3-quinolinecarboxylate

[1075] A mixture of ethyl2,7-dichloro-4-(chloromethyl)-6-methoxy-3-quinolinecarboxylate (6.9 g,20 mmol) and N-methylpiperazine (9 ml, 80 mmol) is heated to 60° C. for30 min. The reaction mass is diluted with water and extraction iscarried out with ethyl acetate. After decanting, the organic phase iswashed with water, followed by drying over magnesium sulphate, filteringand evaporating under reduced pressure. The residue is taken up inwater, agitated for 15 minutes, filtered, washed with water and driedunder vacuum. The residue is purified by column chromatography (SiO₂,MeOH/CH₂Cl_(2: 5/95) to 8/92). 6.7 g of product, a beige solid, isobtained.

[1076] NMR-¹H (CDCl₃): 1.45 (t, 3H); 2.28 (s, 3H); 2.35-2.70 (m, 8H);3.86 (s, 2H); 4.04 (s, 3H); 4.48 (q, 2H); 7.77 (s, 1H); 8.05 (s, 1H).

[1077] 30.e.{2,7-dichloro-6-methoxy-4-[(4-methyl-1-piperazinyl)methyl]-3-quinolinyl}methanol

[1078] ethyl2,7-dichloro-6-methoxy-4-[(4-methyl-1-piperazinyl)methyl]-3-quinolinecarboxylate(6 g, 14.5 mmol) is dissolved in methylene chloride (120 ml). A molarsolution of diisobutylaluminium hydride in methylene chloride (60 ml, 60mmol) is added slowly. Agitation is carried out for one hour at ambienttemperature. The reaction mass is slowly poured into 300 ml of a 20%solution of Rochelle salt. Agitation is carried out for one hour,followed by filtering on celite and decanting; the organic phase iswashed with a saturated solution of sodium chloride, dried overmagnesium sulphate, filtered and evaporated under reduced pressure. Thesolid is taken up in isopropyl ether, filtered and dried under vacuum.4.3 g of sought product (80%) is obtained, in the form of a yellowsolid.

[1079] NMR-¹H (CDCl₃): 2.27 (s, 3H); 2.30-2.80 (m, 8H); 4.03 (s, 3H);4.08 (s, 2H); 4.96 (s, 2H); 5.95 (s, 1H); 7.37 (s, 1H); 8.05 (s, 1H).

[1080] 30.f.9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1081]{2,7-dichloro-6-methoxy-4-[(4-methyl-1-piperazinyl)methyl]-3-quinolinyl}-methanolis coupled to compound (M) as described in Stage 11.j. of Example 11.The resultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p.>250° C.

[1082] NMR-¹H (DMSO): 0.87 (t, 3H); 1.84 (q, 2H); 2.53 (s, 4H); 3.08 (d,1H); 3.47 (d, 1H); 3.58 (s, 4H); 4.06 (s, 5H); 5.30 (s, 2H); 5.42 (q,2H); 6.03 (s, 1H); 7.31 (s, 1H); 7.91 (s, 1H); 8.16 (s, 1H).

[1083] NMR-C¹³ (DMSO): 8.42; 36.53; 50.65; 53.30; 56.67; 62.00; 66.50;73.32; 99.31; 104.86; 122.32; 126.94; 127.70; 129.83; 130.44; 138.89;144.22; 144.85; 151.05; 153.17; 155.92; 159.19; 172.06.

[1084] IR(KBr): 862; 1063; 1116; 1248; 1595; 1655; 1744; 3449.

Example 319-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1085] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-chloro-4-methoxyaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methoxy-3-quinoline-carboxylate which istreated according to the procedure of Example 30.d., by using morpholineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled to compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A beige solid is obtained, m.p.>250° C.

[1086] NMR-¹H (DMSO): 0.87 (t, 3H); 1.84 (q, 2H); 2.15 (s, 3H); 2.32 (s,4H); 2.50 (s, 4H); 3.08 (d, 1H); 3.47 (d, 1H); 4.06 (s, 5H); 5.29 (s,2H); 5.46 (q, 2H); 6.06 (s, 1H); 7.31 (s, 1H); 7.92 (s, 1H); 8.17 (s,1H).

[1087] NMR-C¹³ (DMSO): 8.42; 36.51; 42.57; 45.93; 50.66; 52.83; 55.05;56.09; 56.72; 61.44; 73.29; 99.30; 104.89; 122.32; 126.89; 127.63;129.85; 130.16; 138.78; 144.18; 144.81; 151.03; 153.10; 155.10; 159.17;172.07.

[1088] IR (KBr): 1055; 1252; 1596; 1655; 1747; 3449.

Example 325-ethyl-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1089] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to aniline in order to produce ethyl2-chloro-4-chloromethyl-3-quinolinecarboxylate which is treatedaccording to the procedure of Example 30.d., with N-methylpiperazine,then reduced according to the method of Example 30.e. into thecorresponding quinolinemethanol. The latter is coupled to compound (M)as described in Stage 11.j. of Example 11. The resultant coupled productis cyclized according to the procedure of Stage 11.k. A yellow solid isobtained, m.p.>260° C.

[1090] NMR-¹H (DMSO): 0.86 (t, 3H); 1.87 (q, 2H); 2.14 (s, 3H);2.32-2.60 (m, 8H); 3.05 (d, 1H); 3.48 (d, 1H); 4.09 (q, 2H); 5.42 (d,1H); 5.52 (d, 1H); 6.03 (se, 1H); 7.40 (s, 1H); 7.72 (t, 1H); 7.85 (t,1H); 8.16 (d, 1H); 8.45 (d, 1H).

[1091] IR (KBr): 1652; 1735; 3424.

Example 335-ethyl-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1092] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to aniline in order to produce ethyl2-chloro-4-chloromethyl-3-quinoline carboxylate which is treatedaccording to the procedure of Example 30.d., by using piperidine insteadof N-methylpiperazine, then reduced according to the method of Example30.e. into the corresponding quinolinemethanol. The latter is coupled tocompound (M) as described in Stage 11.j. of Example 11. The resultantcoupled product is cyclized according to the procedure of Stage 11.k. Ayellow solid is obtained, m.p.>260° C.

[1093] NMR-¹H (DMSO): 0.86 (t, 3H); 1.40 (se, 2H); 1.48 (se, 4H); 1.87(q, 2H); 2.50 (s, 4H); 3.05 (d, 1H); 3.48 (d, 1H); 4.04 (q, 2H); 5.33(s, 2H); 5.42 (d, 1H); 5.51 (d, 1H); 6.07 (se, 1H); 7.75 (t, 1H); 7.85(t, 1H); 8.15 (d, 1H); 8.45 (d, 1H).

[1094] NMR-C¹³ (DMSO): 8.47; 23.50; 25.82; 36.50; 42.50; 50.68; 54.47;58.00; 61.42; 73.35; 99.55; 122.61; 125.31; 127.58; 129.54; 129.55;129.56; 129.57; 140.49; 144.95; 148.63; 152.41; 155.90; 159.23; 172.07.

[1095] IR (KBr): 1659; 1727; 3408.

Example 345-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1096] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to aniline in order to produce ethyl2-chloro-4-chloromethyl-3-quinolinecarboxylate which is treatedaccording to the procedure of Example 30.d., by using morpholine insteadof N-methylpiperazine, then reduced according to the method of Example30.e. into the corresponding quinolinemethanol. The latter is coupled tocompound (M) as described in Stage 11.j. of Example 11. The resultantcoupled product is cyclized according to the procedure of Stage 11.k. Ayellow solid is obtained, m.p.>260° C.

[1097] NMR-¹H (DMSO): 0.86 (t, 3H); 1.87 (q, 2H); 3.05 (d, 1H); 3.30 (s,4H); 3.49 (d, 1H); 3.55 (se, 4H); 4.10 (q, 2H); 5.35 (s, 2H); 5.40 (d,1H); 5.54 (d, 1H); 6.04 (s, 1H); 7.72 (t, 1H); 7.85 (t, 1H); 8.16 (d,1H); 8.47 (d, 1H).

[1098] NMR-C¹³ (DMSO): 8.42; 36.51; 42.57; 50.68; 53.51; 56.06; 61.42;66.41; 73.34; 99.56; 122.64; 125.25; 127.56; 129.81; 139.55; 144.92;148.62; 152.39; 155.89; 159.21; 172.05.

[1099] IR (KBr): 1657; 1729; 3347.

Example 355-ethyl-10-fluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1100] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 4-fluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treatedaccording to the procedure of Example 30.d. with N-methylpiperazine,then reduced according to the method of Example 30.e. into thecorresponding quinolinemethanol. The latter is coupled to compound (M)as described in Stage 11.j. of Example 11. The resultant coupled productis cyclized according to the procedure of Stage 11.k. A yellow solid isobtained, m.p.>275° C.

[1101] NMR-hu 1H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 2.15 (s, 3H); 2.31(m, 4H); 2.50 (m, 4H); 3.07 (d, 1H); 3.48 (d, 1H); 4.04 (m, 2H); 5.31(s, 2H); 5.40 (d, 1H); 5.53 (d, 1H); 6.05 (s, 1H); 7.38 (s, 1H); 7.77(m, 1H); 8.19 (m, 2H).

[1102] NMR-C¹³ (DMSO): 8.43; 36.51; 42.54; 45.89; 50.67; 52.92; 54.93;55.92; 73.32; 99.56; 122.69; 130.43; 132.40; 139.69; 144.70; 145.84;152.19; 155.90; 159.17; 172.05.

[1103] IR(KBr): 836; 1051; 1217; 1291; 1612; 1662; 1726.

Example 365-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizinol1,2-b]quinoline-3,15-dione

[1104] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 4-fluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treatedaccording to the procedure of Example 30.d., by using morpholine insteadof N-methylpiperazine, then reduced according to the method of Example30.e. into the corresponding quinolinemethanol. The latter is coupled tocompound (M) as described in Stage 11.j. of Example 11. The resultantcoupled product is cyclized according to the procedure of Stage 11.k. Abeige solid is obtained, m.p.>250° C.

[1105] NMR-¹H (DMSO): 0.87 (m, 3H); 1.85 (m, 2H); 2.51 (m,4H); 3.06 (d,1H); 3.48 (d, 1H); 3.56 (m, 4H); 4.05 (m, 2H); 5.34 (s, 2H); 5.40 (d,1H); 5.53 (d, 1H); 6.04 (s, 1H); 7.38 (s, 1H); 7.77 (m, 1H); 8.21 (m,2H).

[1106] NMR-C¹³ (DMSO): 8.40; 36.47; 42.52; 50.59; 53.40; 56.14; 61.44;66.41; 73.29; 99.58; 109.05; 109.28; 120.11; 120.37; 122.68; 128.53;130.53; 132.43; 139.13; 144.62; 145.79; 152.07; 155.94; 159.14; 161.59;172.04.

[1107] IR(KBr): 834; 860; 1061; 1118; 1215; 1286; 1516; 1609; 1658;1734.

Example 375-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1108] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d. withN-methylpiperazine, then reduced according to the method of Example30.e. into the corresponding quinolinemethanol. The latter is coupled tocompound (M) as described in Stage 11.j. of Example 11. The resultantcoupled product is cyclized according to the procedure of Stage 11.k. Ayellow solid is obtained, m.p.>260° C.

[1109] NMR-¹H (CDCl₃): 1.00 (t, 3H); 2.00 (q, 2H); 2.35 (s, 3H); 2.50(s, 3H); 2.61 (m, 8H); 3.33 (d, 1H); 3.39 (d, 1H); 3.97 (d, 1H); 4.07(d, 1H); 5.17 (d, 1H); 5.38 (d, 1H); 5.52 (d, 1H); 5.63 (d, 1H); 7.13(d, 1H); 7.28 (s, 1H); 7.99 (d, 1H).

[1110] IR (KBr): 1652; 1747; 3430.

Example 385-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1111] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., by usingmorpholiine instead of N-methylpiperazine, then reduced according to themethod of Example 30.e. into the corresponding quinolinemethanol. Thelatter is coupled to compound (M) as described in Stage 11.j. of Example11. The resultant coupled product is cyclized according to the procedureof Stage 11.k. A yellow solid is obtained, m.p.>260° C.

[1112] NMR-¹H (DMSO+CDCl₃): 1.00 (t, 3H); 2.02 (q, 2H); 2.57 (s, 3H);2.60 (s, 4H); 3.23 (d, 1H); 3.45 (d, 1H); 3.75 (s, 4H); 4.11 (s, 2H);5.44 (s, 2H); 5.47 (d, 1H); 5.65 (d, 1H); 7.62 (s, 1H); 7.73 (d, 1H);8.24 (d, 1H).

[1113] NMR-C¹³ (CF₃CO₂D): 8.35; 13.93; 16.01; 22.24; 25.29; 38.18;43.42; 54.19; 56.04; 56.74; 64.16; 65.09; 77.48; 108.29; 108.57; 128.07;128.70; 129.90; 135.64; 138.03; 139.86; 141.10; 141.56; 147.78; 158.30;161.87; 178.72.

[1114] IR (KBr): 117; 1609; 1654; 1750; 3437.

Example 395-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1115] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., by usingpiperidine instead of N-methylpiperazine, then reduced according to themethod of Example 30.e. into the corresponding quinolinemethanol. Thelatter is coupled to compound (M) as described in Stage 11.j. of Example11. The resultant coupled product is cyclized according to the procedureof Stage 1.k. A yellow solid is obtained, m.p.>260° C.

[1116] NMR-¹H (CF₃CO₂D): 1.09 (s, 3H); 1.70 (t, 1H); 2.03 (m, 5H); 2.25(s, 2H); 2.70 (s, 3H); 3.54 (d, 3H); 3.88 (d, 1H); 4.01 (se, 2H); 5.30(q, 2H); 5.65 (d, 1H); 5.96 (d, 1H); 6.10 (s, 2H); 8.16 (d, 1H); 8.35(s, 1H); 8.61 (s, 1H).

[1117] NMR-C¹³ (CF₃CO₂D): 8.47; 16.07; 20.93; 22.18; 24.76; 38.28;43.53; 54.30; 56.12; 58.33; 64.24; 77.56; 108.37; 111.30; 128.20;129.02; 129.98; 135.60; 138.29; 139.90; 141.60; 142.26; 147.57; 158.28;161.90; 167.63; 170.31; 178.82.

[1118] IR (KBr): 1605; 1657; 1728; 3399.

Example 408-ethyl-8-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione

[1119] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3,4-ethylenedioxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-ethylenedioxy-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d. withN-methylpiperazine, then reduced according to the method of Example30.e. into the corresponding quinolinemethanol. The latter is coupled tocompound (M) as described in Stage 11.j. of Example 11. The resultantcoupled product is cyclized according to the procedure of Stage 11.k. Ayellow solid is obtained, m.p.>260° C.

[1120] NMR-¹H (DMSO): 0.92 (t, 3H); 1.89 (q, 2H); 2.16 (s, 3H); 2.50 (m,8H); 3.12 (d, 1H); 3.50 (d, 1H); 3.95 (s, 2H); 4.47 (s, 4H); 5.19 (q,2H); 5.43 (d, 1H); 5.56 (d, 1H) 7.35 (s, 1H); 7.54 (s, 1H); 7.76 (s,1H).

[1121] NMR-C¹³ (DMSO): 8.45; 24.80; 36.51; 42.48; 45.90; 50.45; 52.98;54.91; 56.10; 61.44; 64.43; 73.30; 99.03; 109.46; 113.51; 121.95;123.51; 127.76; 137.99; 145.00; 145.14; 145.27; 147.24; 150.53; 155.99;159.18; 172.27; 177.00.

[1122] IR (KBr): 1656; 1743; 3422.

Example 419-chloro-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1123] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-chloro-4-fluoroaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., by using morpholineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled to compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A beige solid is obtained, m.p.>250° C.

[1124] NMR-¹H (CF₃COOD): 1.09 (t, 3H); 2.30 (m, 2H); 3.50 (d, 1H); 3.90(d, 1H); 3.98 (d, 4H); 4.36 (s, 4H); 5.38 (q, 2H); 5.64 (d, 1H); 5.96(d, 1H); 6.23 (q, 2H); 8.57 (d, 1H); 8.60 (s, 1H); 8.85 (d, 1H).

[1125] NMR-C¹³ (CF₃COOD): 8.10; 37.80; 43.11; 54.31; 55.78; 63.75;65.11; 77.06; 128.28; 129.55; 130.33; 136.26; 137.11; 138.40; 139.67;139.85; 148.58; 157.54; 159.74; 161.31; 178.00.

[1126] IR(KBr): 848; 1042; 1230; 1609; 1658; 1750; 3310; 3387.

Example 42 Resolution of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1127] A mixture of3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoicacid (19.5 g, 51 mmol) and L-(−)-α-methylbenzylamine (12.12 g, 100 mmol)in absolute ethanol (1 l) is heated to boiling, followed by filteringwhile warm and leaving at rest for 68 hours. The precipitate is filteredand washed with ethanol and with ether to produce 9.8 g of a whitesolid. Analysis by high pressure liquid chromatography on the chiralstationary phase (“Chiral HPLC” on Chiral-AGP column (Chromtech,Stockholm, Sweden) 100×4 mm, eluant 2% acetonitrile in 10 mM phosphatebuffer at pH 6.9, peaks eluting at 4.5 and 7.5 min) reveals two peaksintegrating respectively 24% and 76% of the total area of the two peaks.The solid is taken up in 93% ethanol (350 ml) under reflux, then left atrest for 48 hours. The precipitate is filtered out then washed withethanol and with ether in order to obtain 4.8 g of a white solid whichproduces two peaks integrating respectively 9% and 91% of the total areaof the two peaks using chiral HPLC. The solid is taken up in 50% ethanol(48 ml) under reflux then left at rest for 48 hours. The precipitate isfiltered out then washed with ethanol and with ether in order to produce2.7 g of a white solid which produces two peaks integrating respectively3% and 97% of the total area of the two peaks using chiral HPLC. Thesolid is taken up in 50% ethanol (22 ml) under reflux then left at restfor 48 hours. The precipitate is filtered out then washed with ethanoland with ether in order to produce 1.6 g of a white solid which producestwo peaks integrating respectively 1% and 99% of the total area of thetwo peaks using chiral HPLC. The resultant salt, diastereoisomericallyenriched, taken up in distilled water (20 ml), is treated with aceticacid (0.35 ml, 6.4 mmol) for 15 minutes. The precipitate obtained isfiltered out, washed with water, with acetone and with ether, then driedunder vacuum at 80° C. in order to obtain 1.1 g of a white solid. Thelatter is taken up in absolute ethanol (55 ml) with concentratedhydrochloric acid (11.5 N, 11 ml) added to it in order to obtain ayellow solution which is maintained under agitation at ambienttemperature for 68 hours. The precipitate thus obtained is filtered outand washed with water, with ethanol and with ether, then dried undervacuum at 80° C. in order to obtain 770 mg of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dionewhich is enantiomerically enriched. Analysis by chiral HPLC (Chiral-AGPcolumn, eluted with a 2 to 5% gradient of acetonitrile in 10 mMphosphate buffer at pH 6.9, peaks eluting at 15 and 20 minutes) revealsan enantiomeric excess of 98%. The procedure described above is carriedout again replacing the L-(−)-α-methylbenzylamine withD-(+)-α-methylbenzylamine. In this way the other enantiomer of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dioneis obtained.

Example 4312-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1128] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinoline carboxylate, which istreated according to the procedure of Example 30.d., using1,2,3,6-tetrahydropyridine instead of N-methylpiperazine, then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. The free base thus obtained issuspended in absolute ethanol (50 ml/mmol) then treated with ethanolichydrogen chloride (2.5N, 5 equ.). Initially a yellow solution forms,then a precipitate which is collected by filtering after concentrationto 40% of initial volume, and washed with ether. A light orange solid isobtained, m.p. 264° C.

[1129] NMR-1H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 2.26-2.30 (m, 1H);2.50 (m, 1H); 3.09 (d, 1H); 3.40 (m, 2H); 3.48 (d, 1H); 3.87 (m, 2H);5.05 (m, 2H); 5.48 (q, 2H); 5.65 (m, 2H); 5.89 (m, 1H); 7.42 (s, 1H);8.24-8.30 (m, 1H); 8.76-8.82 (m, 1H); 10.86 (s, 1H).

[1130] NMR-C13 (DMSO): 8.44; 22.36; 36.5; 42.7; 48.71; 50.30; 51.49;61.42; 73.23; 100.16; 112.64; 112.83; 116.05; 120.26; 123.31; 125.29;125.40; 131.17; 133.97; 144.15; 146.26; 146.37; 148.74; 150.52; 151.23;153.20; 153.53; 155.99; 159.04; 172.02.

[1131] IR (KBr): 662; 1064; 1268; 1452; 1523; 1598; 1652; 1743; 2936;3027; 3418.

Example 445-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dionehydrochloride

[1132] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using4-methylpiperidine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A beige solid is obtained, m.p.>250° C.

[1133] NMR-1H (DMSO): 0.9 (m, 6H); 1.1 (m, 2H); 1.4 (m, 1H); 1.55 (d,2H); 1.85 (q, 2H); 2.1 (t, 2H); 2.85 (m, 2H); 3.25 (dd, 2H); 4 (s, 2H);5.3 (s, 2H); 5.45 (dd, 2H); 6.05 (s 1H); 7.35 (s, 1H); 8.15 (dd, 1H);8.45 (dd, 1H).

[1134] IR (KBr): 1454; 1518; 1608; 1658; 1733; 2804; 2926; 3311.

[1135] Suspension of the above free base in absolute ethanol (50ml/mmol) followed by treatment with ethanolic hydrogen chloride (2.5 N,5 equ.) allows the corresponding hydrochloride to be obtained.Initially, a yellow solution forms, then a precipitate which iscollected by filtering after concentration to 40% of the initial volume,then washed with ether. A vivid orange solid is obtained, m.p.>250° C.

[1136] NMR-1H (DMSO): 0.85 (m, 6H); 1.7 (m, 5H); 1.85 (q, 2H); 3.15 (s,1H); 3.25 (dd, 2H); 3,3 (m, 2H); 4.9 (s, 2H); 5.45 (dd, 2H); 5.6 (s,2H); 6.1 (s, 1H); 7.4 (s, 1H); 8.25 (dd, 1H); 8.75 (dd, 1H); 10.35 (s,1H).

[1137] IR (KBr): 1270; 1455; 1523; 1606; 1653; 1742; 2943; 3419.

Example 455-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dionehydrochloride

[1138] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using pyrrolidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A beige solid is obtained, m.p.>250° C.

[1139] NMR-1H (DMSO): 0.85 (t, 3H); 1.7 (s, 4H); 1,85 (q, 2H); 2,55 (s,4H); 3.25 (dd, 2H); 4.15 (d, 2H); 5.35 (s, 2H); 5.45 (dd, 2H); 6.05 (s,1H); 7.35 (s, 1H); 8.15 (dd, 1H); 8.45 (dd, 1H).

[1140] IR (KBr): 1455; 1518; 1605; 1657; 1731; 2801; 2970; 3422.

[1141] Suspension of the above free base in absolute ethanol (50ml/mmol) followed by treatment with ethanolic hydrogen chloride (2.5 N,5 equ.) allows the corresponding hydrochloride to be obtained.Initially, a yellow solution forms, then a precipitate which iscollected by filtering after concentration to 40% of the initial volume,then washed with ether. A light orange solid is obtained, m.p.>250° C.

[1142] NMR-1H (DMSO): 0.85 (t, 3H); 1.9 (m, 4H); 2.1 (s, 2H); 3.25 (dd,2H); 3.3 (m, 2H) 3.55 (m, 2H); 5.05 (s, 2H); 5.45 (dd, 2H); 5.6 (s, 2H);6.1 (s, 1H); 7.4 (s, 1H); 8.3 (dd, 1H); 8.75 (dd, 1H); 10.75 (s, 1H).

[1143] IR (KBr): 1454; 1522; 1603; 1653; 1743; 2970; 3394.

Example 465-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1144] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p.>250° C.

[1145] NMR-1H (CDCl₃+CD₃OD): 0.99 (t, 3H); 2.00 (q, 2H); 2.32 (s, 3H);3.24 (d, 1H); 3.37 (s, 1H); 3.42 (d, 1H); 4.04 (s, 2H); 5.37 (s, 2H);5.43 (d, 1H); 5.64 (d, 1H); 7.56 (s, 1H); 7.84 (dd, 1H); 8.22 (dd, 1H).

[1146] NMR-C13 (CDCl₃+CD₃OD): 7.87; 36.11; 42.16; 45.33; 52.67; 54.52;56.47; 61.97; 73.26; 101.17; 110.81; 115.49; 122.93; 128.63; 139.83;144.28; 146.40; 149.27; 151.27; 151.64; 152.31; 153.82; 156.50; 159.71;172.56.

[1147] IR(KBr): 1607; 1656; 1732; 2795; 3411.

Example 475-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1148] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using piperidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A light green solid is obtained, m.p. 266-268° C.

[1149] NMR-1H (DMSO): 0.86 (t, 3H); 1.42-1.49 (m, 6H); 1.85 (q, 2H);2.47 (m, 4H); 3.06 (d, 1H); 3.48 (d, 1H); 4.00 (q, 2H); 5.31 (s, 2H);5.46 (dd, 2H); 6.04 (s, 1H); 7.37 (s, 1H); 8.14 (m, 1H); 8.46 (m, 1H).

[1150] NMR-C13 (DMSO): 8.43; 24.01; 25.8; 36.52; 42.56; 50.60; 54.29;56.91; 61.41; 73.30; 99.81; 111.86; 115.67; 122.94; 130.10; 140.66;144.49; 146.12; 153.18; 155.86; 159.14; 172.03.

[1151] IR(KBr): 1258; 1452; 1517; 1607; 1661; 1731; 2950; 3480.

Example 4812-[(dimethylamino)methyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1152] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3,4-difluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using dimethylamineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A light beige solid is obtained, m.p.>270° C.

[1153] NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.25 (s, 6H); 3.08 (d,1H); 3.47 (d, 1H); 3.95 (q, 2H); 5.28 (s, 2H); 5.46 (dd, 2H); 6.06 (s,1H); 7.37 (s, 1H); 8.14 (s, 1H); 8.42 (s, 1H).

[1154] NMR-C13 (DMSO): 8.42; 14.06; 33.36; 45.44; 50.57; 61.40; 65.14;72.05; 72.93; 73.30; 99.82; 99.95; 115.78; 115.85; 122.96; 125.01;130.08; 140.56; 144.54; 146.16; 155.86; 159.19; 172.03.

[1155] IR (KBr): 1516; 1613; 1654; 1731; 3450.

Example 499-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1156] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using morpholineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p.>300° C.

[1157] NMR-1H (DMSO): 0.87 (t, 3H); 1.84 (q, 2H); 2.50 (s, 4H); 2.58 (s,3H); 3.07 (d, 1H); 3.46 (d, 1H); 3.57 (s, 4H); 4.08 (dd, 2H); 5.30 (s,2H); 5.51 (dd, 2H); 6.06 (s, 1H); 7.35 (s, 1H); 8.15 (s, 1H): 8.41 (s,1H).

[1158] NMR-C13 (DMSO): 8.42; 20.57; 36.51; 42.55; 50.76; 53.46; 55.86;61.42; 66.42; 73.29; 99.73; 122.78; 128.40; 130.10; 135.31; 136.26;139.36 144.61; 147.79; 152.81; 155.86; 159.16; 172.04.

[1159] IR (KBr): 1613; 1657; 1736; 3432.

Example 509-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1160] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p. 262-268° C.

[1161] NMR-1H (DMSO): 0.87 (t, 3H); 1.86 (q, 2H); 2.15 (s, 3H); 2.20-260(m, 8H); 2.60 (s, 3H); 3.05 (d, 1H); 3.49 (d, 1H); 4.09 (dd, 2H); 5.32(s, 2H); 5.50 (dd, 2H); 6.05 (s, 1H); 7.37 (s, 1H); 8.21 (s, 1H); 8.43(s, 1H).

[1162] NMR-C13 (DMSO): 8.42; 20.56; 36.50; 42.55; 45.91; 50.81; 53.00;54.94; 55.65; 61.43; 73.29; 79.36; 99.69; 122.75; 126.32; 128.37;129.84; 135.25; 136.23; 139.87; 144.57; 147.75; 152.76; 155.87; 159.15;172.04.

[1163] IR (KBr): 1607; 1658; 1733; 3424.

Example 5112-{[benzyl(methyl)amino]methyl}-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1164] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., usingN-methylbenzylamine instead of N-methylpiperazine, then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p. 275-278° C.

[1165] NMR-1H (DMSO): 0.88 (t, 3H); 1.85 (m, 2H); 2.13 (s, 3H); 2.55 (s,3H); 3.10 (d, 1H); 3.50 (d, 1H); 3.67 (s, 2H); 4.05 (dd, 2H); 5.30 (s,2H); 5.39-5.57 (dd, 2H); 6.05 (s, 1H); 7.36 (m, 6H); 8.15 (s, 1H); 8.31(s, 1H).

[1166] NMR-C13 (DMSO): 9.10; 21.15; 37.20; 42.86; 43.23; 51.32; 55.78;62.10; 62.88; 73.99; 80.05; 100.44; 123.47; 126.99; 127.32; 128.09;129.17; 129.96; 130.86; 135.75; 136.84; 139.51; 140.67; 145.38; 148.54;153.50; 156.54; 159.85: 172.73.

[1167] IR (KBr): 1609; 1655; 1729; 3395.

Example 5212-[(4-benzyl-1-piperazinyl)methyl]-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1168] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., usingN-benzylpiperazine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A beige solid is obtained, m.p. 244-249° C.

[1169] NMR-1H (DMSO): 0.86 (t, 3H); 1.83 (m, 2H); 2.38-2.60 (m, 8H);2.57 (s, 3H); 3.08 (d, 1H); 3.46 (s ,2H); 4.08 (m, 2H); 5.30 (s, 2H);5.51 (dd, 2H); 6.05 (s, 1H); 7.30 (m, 6H); 8.16 (s, 1H); 8.40 (s, 1H).

[1170] NMR-C13 (DMSO): 9.10; 21.23; 37.19; 43.21; 51.48; 53.54; 53.80;56.35; 62.09; 62.84; 73.97; 97.67; 100.39; 123.45; 127.05; 127.75;129.02 129.63; 130.61; 135.95; 136.93; 139.14; 140.52; 145.27; 148.45;153.47; 156.52; 159.83; 172.72.

[1171] IR (KBr): 1567; 1587; 1652; 1748; 3422.

Example 539-chloro-5-ethyl-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1172] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using piperidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p. 255° C.(dec).

[1173] NMR-1H (DMSO): 0.86 (t, 3H); 1.50 (m, 6H); 1.84 (m, 2H); 2.50 (m,4H); 2.58 (s, 3H); 3.05 (d, 1H); 3.45 (d, 1H); 4.04 (m, 2H); 5.32 (s,2H); 5.51 (dd, 2H); 6.10 (s, 1H); 7.37 (s, 1H); 8.20 (s, 1H); 8.42 (s,1H).

[1174] NMR-C13 (DMSO): 9.11; 21.24; 24.70; 26.50; 37.20; 43.23; 51.43;55.10; 57.21; 62.09; 73.99; 98.05; 100.38; 123.44; 127.10; 129.12;130.59; 135.89; 136.91; 140.99; 145.31; 148.50; 153.52; 156.51; 159.85;172.73.

[1175] IR (KBr): 1601; 1654; 1728; 3436.

Example 5412-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1176] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 4-fluoroaniline in order to produce ethyl2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treatedaccording to the procedure of Example 30.d., using N-benzylpiperazineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A white solid is obtained, m.p. 262° C.

[1177] NMR-1H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 2.37 (s, 4H); 2.37 (s,4H); 3.07 (d, 1H); 3.45 (s, 2H); 3.47 (d, 1H); 4.08 (q, 2H); 5.32 (s,2H); 5.46 (dd, 2H); 6.03 (s, 1H); 7.35 (m, 5H); 7.38 (s, 1H); 7.77 (m,1H); 8.20 (m, 2H).

[1178] NMR-C13 ()MSO): 8.41; 36.49; 42.53; 50.65; 52.82; 53.03; 55.95;61.41; 62.14; 72.3; 99.55; 109.31; 120.14; 120.40; 122.70; 127.05;128.32 128.55; 128.96; 130.40; 138.42; 139.65; 144.66; 145.83; 152.15;155.89; 159.15; 161.57; 172.02.

[1179] IR (KBr): 740; 834; 1071; 1193; 1220; 1288; 1360; 1451; 1516;1592; 1655; 1749; 2813; 2950; 3434.

Example 5512-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1180] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., usingN-benzylpiperazine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A light beige solid is obtained, m.p. 259° C.

[1181] NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.38 (m, 4H); 2.50 (s,4H) 3.06 (d, 1H); 3.36 (s, 3H); 3.46 (s, 2H); 3.47 (d, 1H); 4.07 (q,2H); 5.29 (s, 2H); 5.46 (d, 2H); 6.02 (s, 1H); 7.23-7.35 (m, 6H); 7.8(d, 1H); 8.35 (d, 1H).

[1182] NMR-C13 (DMSO): 8.40; 15.45; 36.47; 42.54; 50.7; 52.84; 53.13;55.81; 61.4; 62.14; 73.29; 99.57; 112.45; 122.61; 124.73; 127.05;128.32; 128.96; 138.45; 139.81; 1444.68; 152.63; 155.85; 159.15; 172.02.

[1183] IR(KBr): 1013; 1069; 1169; 1241; 1266; 1475; 1577; 1594; 1655;1744.

Example 5612-[(dimethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1184] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., usingdimethylamine instead of N-methylpiperazine, then reduced according tothe method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A light beige solid is obtained, m.p. 184-190°C.

[1185] NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.26 (s, 6H); 2.5 (s,3H); 3.05 (d, 1H); 3.48 (d, 1H); 3.98 (q, 2H); 5.28 (s, 2H); 5.46 (dd,2H); 6.06 (s, 1H); 7.37 (s, 1H); 7.84 (d, 1H); 8.35 (d, 1H).

[1186] NMR-C13 (DMSO): 8.45; 15.50; 36.52; 45.59; 50.62; 57.36; 61.43;73.33, 99.66; 112.29; 112.50; 122.67; 124.71; 126.99; 127.20; 127.44;129.08; 140.16; 144.80; 148.82; 152.71; 155.89; 159.22; 160.75; 172.07.

[1187] IR (KBr): 1448; 1595; 1653; 1749; 2950; 3438.

Example 5712-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1188] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., usingdiethylamine instead of N-methylpiperazine, then reduced according tothe method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A light beige solid is obtained, m.p.>270° C.

[1189] NMR-1H (DMSO): 0.87 (t, 3H); 1.04 (t, 6H); 1.86 (q, 2H); 2.50 (q,2H); 2.54 (s, 3H); 2.56 (q, 2H); 3.08 (d, 1H); 3.48 (d, 1H); 4.11 (q,2H); 5.25 (s, 2H); 5.46 (dd, 2H); 6.05 (s, 1H); 7.35 (s, 1H); 7.80 (d,1H); 8.36 (d, 1H).

[1190] NMR-C13 (DMSO): 8.45; 11.68; 11.78; 15.43; 15.57; 36.5; 42.5;46.68; 46.83; 46.99; 50.77; 51.85; 52.08; 61.44; 73.30; 99.60; 112.18;112.36; 122.6; 124.6; 126.9; 127.1; 128.8; 141.45; 144.6; 148.6; 148.7;152.65 155.9; 159.1; 160.7; 163.2; 172.1.

[1191] IR (KBr): 1217; 1295; 1448; 1463; 1507; 1609; 1660; 1725; 2971;3559.

[1192] Suspension of the above free base in absolute ethanol (50ml/mmol) followed by treatment with ethanolic hydrogen chloride (2.5 N,5 equ.) allows the corresponding hydrochloride to be obtained.Initially, a yellow solution forms, then a precipitate which iscollected by filtering after concentration to 40% of the initial volume,then washed with ether. A vivid yellow solid is obtained, m.p. 269-272°C.

[1193] NMR-1H (DMSO): 0.87 (t, 3H); 1.34 (m, 1H); 1.86 (q, 2H); 2.56 (s,3H); 3.07 (d, 1H); 3.19 (m, 2H); 3.39 (m, 2H); 3.49 (d, 1H); 4.97 (m,2H); 5.41 (d, 1H); 5.54 (d, 1H); 5.58 (s, 2H); 6.08 (s, 1H); 7.42 (s,1H); 7.96 (d, 1H); 8.43 (d, 1H); 10.38 (s, 1H).

[1194] IR (KBr): 1039; 1070; 1226; 1282; 1509; 1654; 1724; 1744; 2921;3409; 3489.

Example 585-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1195] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., using4-methylpiperidine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A yellow solid is obtained, m.p.>250° C.

[1196] NMR-1H (DMSO): 1.00-0.80 (complex, 6H); 1.12 (q, 1H); 1.37 (s,1H); 1.57 (d, 3H); 1.85 (q, 2H); 2.13 (t, 2H); 2.82 (s, 1H); 2.85 (s,1H); 3.05 (d, 1H); 3.25 (s, 3H); 3.48 (d, 1H); 4.04 (q, 2H); 5.28 (s,2H); 5.39 (d, 1H); 5.52 (d, 1H); 6.03 (s, 1H); 7.36 (s, 1H); 7.82 (d,1H); 8.40 (d, 1H).

[1197] NMR-C13 (DMSO): 0.29; 8.43; 13.68; 15.48; 19.40; 21.93; 23.23;30.39; 34.20; 36.52; 42.55; 50.67; 53.84; 56.29; 57.67; 61.40; 73.32;99.59; 112.49; 122.62; 124.80; 127.18; 129.10; 140.31; 144.58; 148.64;152.69; 155.84; 159.19; 172.05.

[1198] IR (KBr): 1597; 1653; 1747; 3446.

Example 595-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1199] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., usingpyrrolidine instead of N-methylpiperazine, then reduced according to themethod of Example 30.e. into the corresponding quinolinemethanol. Thelatter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A yellow solid is obtained, m.p.>250° C.

[1200] NMR-1H (DMSO): 0.86 (t, 3H); 1.72 (s, 4H); 1.85 (q, 2H); 2.57 (s,4H); 3.05 (d, 1H); 3.28 (s, 3H); 3.48 (d, 1H); 4.18 (q, 2H); 5.28 (s,2H); 5.39 (d, 1H); 5.52 (d, 1H); 6.03 (s, 1H); 7.36 (s, 1H); 7.82 (d,1H); 8.35 (d, 1H).

[1201] NMR-C13 (DMSO): 0.37; 8.47; 15.57; 23.48; 36.53; 42.61; 50.61;53.45; 54.09; 61.42; 73.33; 99.59; 112.37; 122.64; 124.51; 127.00;127.25; 128.63; 140.65; 144.77; 148.65; 152.73; 155.87; 159.20; 162.00;167.00; 172.07.

[1202] IR (Kflr): 1608; 1656; 1729; 3400.

Example 6012-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1203] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., using1,2,3,6-tetrahydropyridine instead of N-methylpiperazine, then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p.>250° C.

[1204] NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.08 (s, 2H); 3.03 (s,2H); 3.05 (d, 1H); 3.28 (s, 3H); 3.48 (d, 1H); 4.12 (d, 1H); 5.28 (s,2H); 5.39 (d, 1H); 5.52 (d, 1H); 5.64 (d, 1H); 6.03 (s, 1H); 7.36 (s,1H); 7.83 (d, 1H); 8.36 (d, 1H).

[1205] NMR-C13 (DMSO): 8.45; 15.54; 25.84; 36.54; 42.55; 49.78; 50.68;52.52; 55.81; 61.42; 73.33; 99.62; 112.53; 122.66; 124.78; 125.03;127.09; 127.19; 131.73; 139.98; 144.76; 148.79; 152.73; 155.86; 159.19;160.76; 163.25; 172.07.

[1206] IR (KBr): 1605; 1656; 1733; 3451.

Example 6112-[(diisobutylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1207] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methylaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., usingdiisobutylamine instead of N-methylpiperazine, then reduced according tothe method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A yellow solid is obtained, m.p.>250° C.

[1208] NMR-1H (DMSO): 0.75 (d. 12H); 0.87 (t, 3H); 1.83 (m, 4H); 2.15(d, 1H); 2.48 (s, 3H); 3.06 (d, 1H); 3.47 (d, 1H); 4.01 (q, 2H); 5.28(s, 2H); 5.39 (d, 1H); 5.53 (d, 1H); 6.03 (s, 1H); 7.37 (s, 1H); 7.83(d, 1H); 8.49 (d, 1H).

[1209] NMR-C13 (DMSO): 9.09; 16.14; 21.73; 26.57; 26.70; 37.15; 43.14;51.05; 55.49; 62.08; 64.74; 73.98; 100.42; 113.03; 123.38; 125.58;127.12; 127.32; 128.59; 130.27; 141.32; 145.51; 149.38; 149.51; 153.20;156.62; 159.86; 161.31; 163.79; 172.72.

[1210] IR (KBr): 1599; 1656; 1747; 2796; 3448.

Example 625-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1211] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A light yellow solid isobtained, m.p. 274° C.

[1212] NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.15 (s, 3H); 2.31 (m,4H); 2.47 (m, 4H); 3.06 (d, 1H); 3.47 (d, 1H); 4.05 (m, 2H); 4.05 (s,3H); 5.28 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.35 (s, 1H); 7.87 (d,1H); 7.94 (d, 1H).

[1213] NMR-C13 (DMSO): 8.44; 36.53; 45.58; 45.95; 50.68; 52.86; 55.07;56.20; 56.47; 61.45; 73.32; 99.19; 105.90; 113.74; 113.91; 122.22;125.60; 129.46; 138.83; 144.51; 144.62; 144.94; 147.85; 147.98; 150.96;152.82; 155.34; 155.96; 159.19; 172.09.

[1214] IR (KBr): 1270; 1515; 1594; 1648; 1747; 2950; 3438.

Example 635-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1215] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-fluoro-4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate whichis treated according to the procedure of Example 30.d., using piperidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A light green solid is obtained, m.p.>275° C.

[1216] NMR-1H (DMSO): 0.86 (t, 3H); 1.42-1.50 (m, 6H); 1.84 (q, 2H);2.50 (m, 4H); 3.05 (d, 1H); 3.48 (d, 1H); 4.03 (s, 2H); 4.05 (s, 3H);5.30 (s, 2H); 5.45 (dd, 2H); 6.02 (s, 1H); 7.35 (s, 1H); 7.9 (d, 1H)7.99 (d, 1H).

[1217] NMR-C13 (DMSO): 8.44; 24.07; 25.9; 36.54; 42.57; 50.60; 54.26;56.40; 57.11; 61.42; 73.33; 99.17; 105.97; 113.75; 113.92; 122.21;125.66; 129.46; 139.23; 144.54; 144.98; 147.94; 151.0; 152.82; 155.34;155.89; 159.20; 172.07.

[1218] IR (KBr): 860; 1057; 1270; 1514; 1656; 1748; 2857; 2932; 3397.

[1219] Suspension of the above free base in absolute ethanol (50ml/mmol) followed by treatment with ethanolic hydrogen chloride (2.5 N,5 equ.) allows the corresponding hydrochloride to be obtained.Initially, a yellow solution forms, then a precipitate which iscollected by filtering after concentration to 40% of the initial volume,then washed with ether. A light yellow solid is obtained, m.p. 264° C.

[1220] NMR-1H (DMSO): 0.86 (t, 3H); 1.42 (m, 1H); 1.70-1.85 (m, 7H);3.06 (d, 1H); 3.33 (m, 4H); 3.47 (m, 1H); 4.19 (s, 3H); 5.00 (s, 2H);5.40 (d, 1H); 5.54 (d, 1H); 5.62 (s, 2H); 6.02 (s, 1H); 7.37 (s, 1H);7.95-8.04 (m, 2H); 10.46(s, 1H).

[1221] NMR-C13 (DMSO): 9.12; 22.11; 22.91; 37.63; 43.20; 52.27; 53.20;54.00; 54.75; 57.91; 58.15; 62.12; 62.78; 73.97; 100.06; 106.96; 107.14;114.80; 123.20; 126.58; 130.48; 134.14; 145.33; 145.48; 149.49; 149.62;151.76; 153.84; 156.36; 156.69; 159.76; 172.73.

[1222] IR(KBr): 1010; 1072; 1240; 1271; 1469; 1511; 1574; 1598; 1648;1734; 2525; 2944; 3430; 3507.

Example 649-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1223] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-chloro-4-methoxyaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using dimethylamineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p.>250° C.

[1224] NMR-1H (DMSO): 0.86 (t, 3H); 1.84 (q, 2H); 2.29 (s, 6H); 3.06 (d,1H); 3.42 (d, 1H); 3.98 (q, 2H); 4.05 (s, 3H); 5.27 (s, 2H); 5.45 (s,2H); 5.95 (s, 1H); 7.32 (s, 1H); 7.82 (s, 1H); 8.19 (s, 1H).

[1225] NMR-C13 (DMSO): 8.41; 36.50; 42.55; 45.58; 50.62; 56.70; 57.42;61.42; 73.29; 99.28; 104.66; 122.34; 126.92; 127.55; 129.89; 130.04;139.19 144.20; 144.81; 151.08; 153.15; 155.91; 159.18; 172.04.

[1226] IR(KBr): 1048; 1242; 1482; 1611; 1659; 1730; 3301; 3417.

Example 659-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1227] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-chloro-4-methoxyaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using piperidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. The free base thus obtained is suspended in absolute ethanol(50 ml/mmol) then treated with ethanolic hydrogen chloride (2.5 N, 5equ.). Initially a yellow solution forms, then a precipitate which iscollected by filtering after concentration to 40% of initial volume, andwashed with ether. An orange solid is obtained, m.p.>250° C.

[1228] NMR-1H (DMSO): 0.86 (t, 3H); 1.43 (q, 1H); 1.70 (d, 1H); 1.76 (m,2H); 1.86 (m, 4H); 3.07 (d, 1H); 3.28 (m, 2H); 3.47 (m, 3H); 4.20 (s,3H); 5.00 (q, 2H); 5.41 (d, 1H); 5.54 (d, 1H); 5.62 (s, 1H); 6.10 (s,1H); 7.36 (s, 1H); 7.88 (s, 1H); 8.31 (s, 1H).

[1229] NMR-C13 (CF₃COOD): 8.44; 22.11; 24.79; 38.27; 43.51; 54.28;56.01; 58.51; 58.75; 64.23; 77.59; 104.22; 110.49; 124.68; 129.44;131.91; 136.61; 140.01; 141.33; 144.72; 158.25; 161.10; 161.89; 178.85.

[1230] IR (KBr): 1079; 1288; 1488; 1562; 1578; 1648; 1747; 2936; 3406.

Example 6612-[3,6-dihydro-1(2-H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1231] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using1,2,3,6-tetrahydropyridine instead of N-methylpiperazine, then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. The free base thus obtained issuspended in absolute ethanol (50 ml/mmol) then treated with ethanolichydrogen chloride (2.5 N, 5 equ.). Initially a yellow solution forms,then a precipitate which is collected by filtering after concentrationto 40% of initial volume, and washed with ether. A yellow solid isobtained, m.p.>250° C.

[1232] NMR-1H (DMSO): 0.86 (t, 3H); 1.87 (q, 2H); 2.32 (m, 1H); 3.07 (d,1H); 3.48 (m, 3H); 3.89 (m, 8H); 4.06 (s, 3H); 5.08 (m, 2H); 5.40 (d,1H); 5.54 (d, 1H); 5.63 (q, 2H); 5.67 (d, 2H); 5.93 (d, 2H); 7.37 (s,1H); 7.59 (q, 1H); 7.79 (d, 1H); 8.14 (d, 1H); 10.80 (s, 1H).

[1233] NMR-C13 (DMSO): 8.47; 25.97; 36.40; 42.55; 49.75; 50.25; 50.61;52.36; 56.05; 61.44; 73.36; 98.95; 103.74; 121.99; 122.29; 124.98;125.50; 128.84; 129.84; 131.18; 138.47; 144.63; 145.18; 150.01; 155.93;159.24; 172.10.

[1234] IR (KBr): 827; 1065; 1228; 1289; 1592; 1653; 1746; 2363; 3373.

Example 675-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1235] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using4-methylpiperidine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A yellow solid is obtained, m.p.>250° C.

[1236] NMR-1H (CF₃COOD): 1.17 (m, 6H); 1.62 (m, 2H); 1.89 (s, 1H); 2.07(q, 2H); 2.25 (m, 2H); 3.54 (m, 3H); 3.89 (d, 1H); 4.02 (s, 2H); 4.19(s, 3H); 7.94 (s, 1H); 8.10 (m, 1H); 8.29 (s, 1H); 8.50 (m, 1H).

[1237] NMR-C13 (CF₃COOD): 8.43; 13.79; 17.43; 20.89; 30.01; 32.85;38.26; 43.50; 54.13; 56.09; 57.87; 58.27; 64.22; 77.57; 107.37; 110.56;125.75 129.36; 129.42; 132.78; 136.04; 136.65; 139.91; 140.38; 144.31;158.30; 161.94; 164.90; 178.84.

[1238] IR (KBr): 825; 1056; 1230; 1260; 1516; 1641; 1655; 1736; 2921;3395.

Example 685-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1239] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., then reducedaccording to the method of Example 30.e. into the correspondingquinolinemethanol. The latter is coupled with compound (M) as describedin Stage 11.j. of Example 11. The resultant coupled product is cyclizedaccording to the procedure of Stage 11.k. A yellow solid is obtained,m.p. 215-219° C.

[1240] NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (m, 2H); 2.15 (s, 3H); 2.35 (m,4H); 2.5 (m, 4H); 3.25 (dd, 2H); 3.95 (s, 3H); 4.05 (s, 2H); 5.3 (s,2H); 5.45 (dd, 2H); 6 (s, 1H); 7.3 (s, 1H); 7.5 (d, 1H); 7.7 (s, 1H);8.05 (d, 1H).

[1241] NMR-C13 (DMSO): 9.12; 14.36; 20.08; 23.93; 46.61; 51.35; 53.58;55.71; 56.34; 56.73; 58.37; 62.11; 74.03; 99.62; 104.49; 122.66; 123.11;129.54; 130.53; 131.82; 139.05; 145.3; 145.86; 150.67; 156.62; 158.71;159.91; 172.77.

[1242] IR (KBr): 1590; 1624; 1655; 1744; 2801; 2935; 3423.

Example 695-ethyl-5-hydroxy-10-methoxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1243] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using pyrrolidineinstead of N-methylpiperazine, then reduced according to the method ofExample 30.e. into the corresponding quinolinemethanol. The latter iscoupled with compound (M) as described in Stage 11.j. of Example 11. Theresultant coupled product is cyclized according to the procedure ofStage 11.k. A yellow solid is obtained, m.p.>250° C.

[1244] NMR-1H (DMSO): 0.85 (t, 3H); 1.7 (s, 4H); 1.85 (q, 2H); 2.55 (s,4H); 3.25 (dd, 2H); 3.9 (s, 3H); 4.15 (s, 2H); 5.25 (s, 2H); 5.45 (dd,2H); 6 (s, 1H); 7.35 (s, 1H); 7.5 (d, 1H); 7.7 (s, 1H); 8.05 (d, 1H).

[1245] NMR-C13 (DMSO): 9.68; 24.74; 51.8; 54.71; 55.25; 56.3; 56.87;62.3; 62.64; 74.5; 100.14; 104.8; 104.92; 123.19; 123.45; 129.79;130.49; 132.32; 132.50; 140.5; 145.83; 146.4; 151.27; 157.15; 159.25;160.45; 173.3.

[1246] IR (KBr): 1255; 1516; 1535; 1613; 1655; 1735; 3438; 3762; 3830.

Example 7012-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1247] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 4-methoxyaniline in order to produce ethyl2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., usingN-benzylpiperazine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A beige solid is obtained, m.p.>250° C.

[1248] NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.45 (s, 2H); 2.4 (m,4H); 2.55 (m, 4H); 3.25 (dd, 2H); 3.45 (s, 2H); 3.95 (s, 3H); 4.05 (s,2H); 5.3 (s, 2H); 5.45 (dd, 2H); 6 (s, 1H); 7.3 (m, 6H); 7.5 (d, 1H);7.75 (s, 1H); 8 (d, 1H).

[1249] NMR-C13 (DMSO): 7.38; 49.56; 51.89; 54.46; 54.82; 54.98; 55.1;60.1; 60.35; 61.11; 72.26; 97.86; 102.6; 102.76;;120.9; 121; 121.2;121.4; 126; 127.25; 127.77; 127.88; 128.76; 130.13; 130.2; 137.25;137.36; 143.53 144.08; 148.86; 156.86; 156.95; 158.15; 171.02.

[1250] IR (KBr): 1235; 1259; 1517; 1586; 1614; 1654; 1747; 2927; 3450;3762; 3848.

[1251] Suspension of the above free base in absolute ethanol (50ml/mmol) followed by treatment with ethanolic hydrogen chloride (2.5 N,5 equ.) allows the corresponding hydrochloride to be obtained.Initially, a yellow solution forms, then a precipitate which iscollected by filtering after concentration to 40% of the initial volume,then washed with ether. A yellow solid is obtained, m.p.>250° C.

[1252] NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 2.5 (s, 2H); 2.65 (m,2H); 3 (m, 2H); 3.2 (m, 2H); 3.35 (dd, 2H); 3.35 (s, 2H); 3.95 (s, 3H);4.15 (s, 2H); 4.3 (s, 2H); 5.3 (s, 2H); 5.45 (dd, 2H); 7.3 (s, 1H); 7.4(s, 2H); 7.55 (m, 2H); 7.7 (s, 1H); 8.05 (d, 1H); 10.45 (s, 1H).

[1253] IR (KBr): 1207; 1233; 1439; 1449; 1458; 1508; 1610; 1620; 1655;1727; 3398.

Example 719-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1254] The procedure described in Examples 30.a., 30.b. and 30.c. isapplied to 3-chloro-4-methylaniline in order to produce ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which istreated according to the procedure of Example 30.d., using4-methylpiperidine instead of N-methylpiperazine, then reduced accordingto the method of Example 30.e. into the corresponding quinolinemethanol.The latter is coupled with compound (M) as described in Stage 11.j. ofExample 11. The resultant coupled product is cyclized according to theprocedure of Stage 11.k. A yellow solid is obtained, m.p.>275° C.

[1255] NMR-1H (DMSO): 0.86 (m, 6H); 1.15 (m, 2H); 1.37 (m, 1H); 1.60 (m,2H); 1.80 (m, 2H); 2.10 (m, 2H); 2.60 (s, 3H); 2.80 (m, 2H); 3.05 (d,1H); 3.48 (d, 1H); 4.02 (s, 2H); 5.30 (s, 2H); 5.45 (dd, 2H); 6.02 (s,1H); 7.40 (s, 1H); 8.20 (s, 1H); 8.40 (s, 1H).

[1256] NMR-C13 (DMSO): 9.10; 21.28; 22.61; 31.07; 34.89; 37.18; 43.22;54.53 56.83; 62.10; 73.94; 80.06; 100.43; 123.41; 127.08; 129.11;130.58; 135.88; 136.89; 141.00; 145.28; 148.49; 153.51; 156.60; 159.85;172.77; 174.05.

[1257] IR (KBr): 1605; 1657; 1734; 3342.

Example 7210-(benzyloxy)-5-ethyl-9-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1258] The procedure described in Stage 11.i. is applied to3-fluoro-4-methoxy-acetanilide in order to produce2-chloro-7-fluoro-6-methoxy-3-quinolinecarbaldehyde which is treatedwith an excess of boron tribromide in dichloromethane at ambienttemperature for 24 hours.2-chloro-7-fluoro-6-hydroxy-3-quinolinecarbaldehyde is obtained, whichis O-benzylated in dimethylformamide in the presence of benzyl bromideand of potassium carbonate in order to produce6-(benzyloxy)-2-chloro-7-fluoro-3-quinolinecarbaldehyde, which isreduced with sodium borohydride in methanol in order to produce thecorresponding quinolinemethanol. The latter is coupled with compound (M)as described in Stage 11.j. of Example 11. The resultant coupled productis cyclized according to the procedure of Stage 11.k. A yellow solid isobtained, m.p.>275° C.

[1259] NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 5.25 (s,2H); 5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.4-7.6 (m, 5H); 7.88(d, 1H); 7.95 (d, 1H); 8.56 (s, 1H).

Example 735-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1260] The hydrogenolysis procedure of Example 14 is applied to thecompound of Example 72. A yellow solid is obtained, m.p.>275° C.

[1261] NMR-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 5.25 (s,2H); 5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.8 (d, 1H); 7.90 (d,1H); 8.56 (s, 1H).

Example 745-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl2-aminoacetate hydrochloride

[1262] 74a.5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl2-[(tert-butoxycarbonyl)amino]acetate

[1263] A mixture of5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(200 mg, 0.526 mmol, example 18), N-Boc-glycine (185 mg, 1.051 mmol) anda catalytic quantity of 4-dimethylaminopyridine (20 mg) in anhydrouspyridine (10 ml) is treated at 0° C. and under argon withdicyclohexylcarbodiimide (239 mg, 1.16 mmol), then agitated at ambienttemperature for 48 hours. The volatiles are driven off under vacuum andthe residue is chromatographed (SiO₂, 1% methanol in chloroform) inorder to produce the desired intermediate (40 mg, 14%), a yellow solid.

[1264] NMR-1H (CDCl₃): 1.20 (t, 3H); 1.38 (s, 9H); 1.40-1.70 (m, 2H);3.10 (d, 1H); 4.00 (d, 2H); 4.30 (d, 1H); 5.00 (t, 1H); 5.20 (s, 2H);5.30-5.90 (dd, 2H); 7.20 (s, 1H); 7.50-8.10 (m, 2H); 8.30 (s, 1H).

[1265] 74b.5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl 2-aminoacetate hydrochloride

[1266] The intermediate obtained above (40 mg, 0.072 mmol) in solutionin dichloromethane (10 ml) is maintained at 0° C. and dioxan saturatedwith hydrogen chloride (8 ml) is added dropwise. The yellow suspensionthus formed is maintained under agitation for 2 hours, then thevolatiles are driven off under vacuum. The residue, taken up in water (5ml), is washed with dichloromethane (3×30 ml). The aqueous phase isfrozen and lyophilized in order to produce the expected salt, ahygroscopic yellow solid (20 mg, 50%).

[1267] NMR-1H (CDCl₃): 1.00 (t, 3H); 2.15 (m, 1H); 2.30 (m, 1H); 3.60(d, 1H); 3.90 (d, 1H); 4.15 (s, 2H); 5.10 (s, 2H); 5.40 (d, 1H); 5.70(d, 2H); 7.40 (s, 1H); 7.80 (m, 2H); 8.50 (s, 1H).

Example 755-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-5-yl3-aminopropanoate

[1268] The procedure of Example 74 is applied to5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dioneusing N-Boc-β-alanine instead of N-Boc-glycine, then the Boc protectorof the intermediate thus obtained is cleaved by treatment withtrifluoroacetic acid in dichloromethane. The volatiles are evaporatedoff under vacuum and the residue is taken up in dichloromethane. Theresultant solution is washed with dilute bicarbonate, dried andevaporated. A yellow solid is obtained.

[1269] By applying the method of Examples 74 and 75 to other compounds,for example to those disclosed in the present application, similarresults are obtained. In this way an entire class of campothecinanalogues is accessible in “pro-drug” form.

Example 762,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione

[1270] A suspension of5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(84 mg, example 14) in acetic acid (2.5 ml) is treated with1,3,5-triethylhexahydrotriazine (0.5 ml). The reaction mixture isagitated at 70° C. for 30 minutes, then evaporated under vacuum. Theresidue is taken up in ethanol, filtered and washed with ether. A solidis obtained, m.p.>275° C.

[1271] NMR-1H (DMSO) 0.87 (t, 3H); 1.50 (t, 3H); 1.85 (q, 2H); 2.77 (q,2H); 3.05 (d, 1H); 3.47 (d, 1H); 4.37 (s, 2H); 5.00 (s, 2H); 5.22 (s,2H); 5.45 (dd, 2H); 6.00 (s, 1H); 7.34 (s, 1H); 7.36 (d, 1H); 7.93 (d,1H); 8.53 (s, 1H).

[1272] NMR-C13 (DMSO): 8.46; 13.48; 36.46; 42.49; 45.49; 46.44; 50.75;61.43; 73.33; 82.06; 99.02; 112.90; 122.00; 122.98; 125.42; 127.04;129.04; 130.20; 144.09; 144.97; 149.87; 152.92; 155.98; 172.07.

[1273] IR(KBr): 1045; 1215; 1502; 1604; 1657, 1722.

Example 779-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione

[1274] A suspension of5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(200 mg, example 14) in acetic acid (5 ml) is treated withhexahydro-1,3,5-trimethyltriazine (110 mg). The reaction mixture isagitated at 70° C. for 30 minutes, then evaporated under vacuum. Theresidue is taken up in ethanol, filtered and washed with ether. A solidis obtained, m.p.>275° C.

[1275] NMR-1H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 3.04 (d, 1H); 3.48 (d,1H); 4.33 (s, 2H); 4.93 (s, 2H); 5.28 (s, 2H); 5.45 (dd, 2H); 6.01 (s,1H); 7.35 (s, 1H); 7.38 (d, 1H); 7.94 (d, 1H); 8.49 (s, 1H).

[1276] NMR-C13 (DMSO): 8.46; 36.43; 37.85; 42.55; 48.68; 50.79; 61.43;73.35; 83.82; 99.04; 112.49; 122.04; 123.00; 125.46; 127.14; 129.07;130.27; 144.99; 149.95; 152.46; 155.99; 172.09

[1277] IR (KBr): 1047; 1058; 1219; 1246; 1295, 1439; 1504; 1604, 1655,1735.

Example 782-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione

[1278] A suspension of5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(200 mg, example 14) in acetic acid (5 ml) is treated with1,3,5-tribenzylhexahydrotriazine (285 mg). The reaction mixture isagitated at 70° C. for 30 minutes, then evaporated under vacuum. Theresidue is taken up in ethanol, filtered and washed with ether. A solidis obtained, m.p.>275° C.

[1279] NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 3.47 (d,1H); 3.96 (s, 2H); 4.33 (s, 2H); 5.04 (s, 2H); 5.17 (s, 2H); 5.44 (dd,2H); 6.01 (s, 1H); 7.38 (m, 6H); 7.42 (d, 1H); 7.97 (d, 1H); 8.42 (s,1H).

[1280] NMR-C13 (DMSO): 8.42; 19.96; 36.45; 42.51; 46.36; 50.78; 55.38;61.39; 73.31; 99.00; 112.55; 122.01; 123.08; 125.38; 127.09; 127.47;128.70; 129.14; 130.35; 128.40; 139.19; 144.18; 149.99: 152.84; 155.92;159.24; 172.05.

[1281] IR (KBr): 1056; 1205; 1225; 1248; 1504; 1535; 1599; 1655; 1726.

Example 792-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione

[1282] A suspension of5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-1H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione (200 mg, example 73) in acetic acid (5 ml) is treatedwith 1,3,5-tribenzylhexahydrotriazine (285 mg). The reaction mixture isagitated at 70° C. for 30 minutes, then evaporated under vacuum. Theresidue is taken up in ethanol, filtered and washed with ether. A solidis obtained, m.p.>250° C.

[1283] NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 3.48 (d,1H); 3.95 (s, 2H); 4.45 (s, 2H); 5.20 (s, 4H); 5.45 (dd, 2H); 6.05 (s,1H); 7.40 (s, 7H); 7.90 (d, 1H); 8.45 (s, 1H).

[1284] IR (KBr): 1248; 1451; 15001; 1598; 1657; 1727.

Example 80(+)-5-ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pyridin-3,9-dione[(+)-EHHOPD]

[1285] 80.a. Quinidine salt of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid

[1286] Tertiobutyl3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoate (40 g;100 mmol) is treated with trifluoroacetic acid (150 ml) and the reactionmedium is agitated for 18 hours at 20° C. After evaporation of thetrifluoroacetic acid, methylene chloride (200 ml) is poured in and asaturated solution of sodium bicarbonate is introduced until the pH−7.5-8. After decantation, the aqueous phase is washed with 100 ml ofmethylene chloride. The pH of the aqueous phase is then adjusted to 1 bythe addition of a solution of 6N hydrochloric acid. The product is thenextracted from the aqueous phase with methylene chloride (2 times 200ml). The solution is dried over magnesium sulphate and concentrated. The3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid (31.1g; 90 mmol) thus obtained, taken up in isopropyl alcohol (30 ml), istreated with a solution of quinidine (29.2 g; 90 mmol) in isopropylalcohol (30 ml) at 50° C. under agitation until complete dissolution.Then the reaction medium is left so that temperature reduces to 40° C.,the agitation is stopped and the temperature allowed to drop to 20° C.The medium is taken to 0° C. without agitation then maintained at thistemperature for 16 hours. Then the temperature is allowed to rise to 20°C. and agitation is carried out until crystallization. The medium isdiluted with isopropyl alcohol then filtered. The precipitate is rinsedwith isopropyl alcohol. The salt of the (+) enantiomer precipitates(m=26.6 g) while the salt of the (−) enantiomer remains in solution inthe isopropyl alcohol. Thus the filtrate is recovered which isconcentrated in order to produce an oil (34 g) which is used withoutother purification in the following stage.

[1287] The products are analyzed by HPLC on a 5 μ CHIRAL AGP column (10cm×4 mm) eluted with a 30/920/50 isopropyl alcohol/water/phosphatebuffer mixture, pH=6.5, at a flow rate of 1.2 ml/min, UV detection at280 nm. The retention times obtained are 6.4 minutes for the (−)enantiomer and 2.8 minutes for the (+) enantiomer. The (−)enantiomer/(+) enantiomer ratio is 83/17.

[1288] 80.b.(−)-3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid

[1289] The solution in isopropyl alcohol of the quinidine salt of the(−) enantiomer of3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid(Stage 80.a) is concentrated. The concentrate is taken up in 270 ml ofmethylene chloride and 270 ml of a 1N solution of hydrochloric acid. Thereaction medium is agitated for 16 hours at 20° C. After decantation,the organic phase is concentrated, the concentrate is taken up inmethanol in order to be used in the following stage.

[1290] 13.5 g of product (yield of 87%) and a (−)enantiomer/(+)enantiomer proportion of 85/15 are obtained.

[1291] The HPLC retention times (same protocol as in 1.a.) are:

[1292] (−) enantiomer: 6.4 minutes

[1293] (+) enantiomer: 2.8 minutes

[1294] 80.c.(+)-5-Ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pyridin-3,9-dione:

[1295] (−)-3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoicacid (13.5 g; 39 mmol; Stage 80.b) is put in solution in 87 ml ofmethanol. This solution is poured under nitrogen onto 10% Palladium ondamp carbon at 50% (27.7 g; 13 mmol). The reaction medium is agitatedfor 5 minutes, then it is poured into a solution of ammonium formate(11,5 g; 183 mmol) in 135 ml of methanol. The reaction medium isagitated for 30 minutes while allowing the temperature to rise, then itis heated at 40° C. for 30 minutes. The medium is then filtered on a bedof Clarcel followed by concentrating. 40 ml of toluene is poured inwhich is evaporated off; this operation is repeated in order toeliminate the methanol. The residue thus obtained is taken up in 45 mlof THF. Then a solution of dicyclohexylcarbodiimide (7.180 g; 34.5 mmol)in 20 ml of THF is then poured in. The reaction medium is heated to 50°C. for 1 hour. The mixture is taken to 20° C. then the dicyclohexylureais filtered. The filtrate is concentrated to dryness. The residue is putin solution in 46 ml of acetonitrile, 6.0 g (40.5 mmol.) of sodiumiodide then 5.13 ml (40.5 mmol) of trimethylsilyl chloride are added.The reaction medium is maintained under agitation at ambient temperatuefor 5 hours. Then 28 ml of acetonitrile and 5.6 ml of water are added.The precipitate obtained is filtered then taken up in 1 ml of water, andthe pH is adjusted to 7.5 by the addition of a solution of ammoniumhydroxide. The solid obtained is filtered and dried. M=4.2 g of finalproduct is obtained with a yield of 34% and a (+) enantiomer/(−)enantiomer proportion of 88.4/11.6.

[1296] HPLC analysis is carried out on a Chiralcel OD column 25 cm×4.6mm the eluants used are heptane 600 and ethanol 400, the flow rate is 1ml/min 210 nm. The retention times obtained are

[1297] (−) enantiomer: 7.1 minutes

[1298] (+) enantiomer: 9 minutes.

[1299] The product is taken up in acetone (40 ml), then water (150 ml)is added. The reaction is left to precipitate and 3 g of product isobtained with a (+) enantiomer/(−) enantiomer proportion of 99.4/0.6.

[1300] NMR ¹H (250 MHz, DMSO D6): 0.8 (t, 3H, CH₃—CH₂); 1.65 (m, 2H,CH₂—CH₃); 3.00-3.35 (q, 1H+1H, —CH₂—C═O); 5.3 (q, 2H, CH₂—O); 5.7 (s,—OH); 6.35 (d, aromatic 1H); 7.3 (d, aromatic 1H); 11.7 (s, N—H).

Example 81(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1301] 81.a. N-(3,4-difluorophenyl)acetamide

[1302] A mixture of 3,4-difluoroaniline (50 ml; 0.5 mole) andtriethylamine (70 ml; 0.5 mol) in dichloromethane (1.5 l) is cooled downusing an ice bath. Acetic anhydride (71.5 ml; 0.75 mol) is addeddropwise and the reaction mixture is then agitated for 1 hour at ambienttemperatue. The mixture obtained is then washed successively with water,a 10% solution of sodium bicarbonate and saturated salt water. Theorganic fraction is dried over sodium sulphate and concentrated underreduced pressure. The residue is suspended in pentane, filtered anddried under reduced pressure in order to produce the product in thetitle (78 g; 91% yield) in the form of a whitish solid (M.p. 126-127.5°C.).

[1303] NMR ¹H (DMSO): 2.15 (s, 3H); 7.10-7.65 (m, 2H); 7.65-8.10 (m,1H); 10.30 (wide peak, 1H).

[1304] 81.b. 2-chloro-6,7-difluoro-3-quinoline-3-carbaldehyde

[1305] The general procedure described by Meth-Cohn et al., J. Chem.Soc. Perkin Trans. I, 1981, 1520 and 2509 is used.

[1306] The product of Stage 81.a (32 g; 220 mmol) is added to aVilsmeyer reagent, obtained by the dropwise addition under an argonatmosphere of phosphorus oxychloride

[1307] (103 ml; 1.1 mol) in anhydrous DMF (34 ml; 440 mmol) cooled downin an ice bath and agitated for 30 minutes before leaving thetemperature to rise to ambient temperature. The mixture thus obtained isagitated at 70° C. for 16 hours. After returning the reaction medium toambient temperature, it is added dropwise to a water-ice mixture (400ml) and agitated for 2 hours. The precipitate obtained is filtered andwashed with water, then dried in order to produce the product in thetitle (9 g; 18% yield) in the form of a yellow solid (M.p. 226.5-229°C.).

[1308] NMR ¹H (DMSO): 8.17 (dd, 1H); 8.39 (dd, 1H); 8.97 (d, 1H); 10.34(d, 1H).

[1309] IR (KBr): 888, 1061, 1262, 1507, 1691 cm⁻¹.

[1310] 81.c. 2-chloro-6,7-difluoro-3-quinolylmethanol

[1311] A suspension of the product of Stage 81.b (9 g; 39 mmol) inmethanol (400 ml) is treated with sodium borohydride (2 g; 53 mmol) atambient temperature for half an hour. The excess borohydride isdestroyed with acetic acid (2 ml). The volatile substances areeliminated under reduced pressure. The residue is dissolved in ethylacetate (500 ml), the mixture obtained then being washed successivelywith a dilute solution of sodium bicarbonate, water and saturated saltwater, followed by drying over magnesium sulphate and concentrationunder reduced pressure. The residue is recrystallized from1,2-dichloroethane in order to produce the product in the title (8 g;80% yield) in the form of a beige solid (M.p. 166.5-167° C.).

[1312] NMR ¹H (DMSO): 4.67 (d, 2H); 5.80 (t, 1H); 8.01 (dd, 1H); 8.22(dd, 1H); 8.48 (s, 1H).

[1313] IR (KBr): 871, 1038, 1253, 1513 cm⁻¹.

[1314] 81.d.(+)-8-(2-chloro-6,7-difluoro-3-quinolinemethanol)-5-ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pyridine-3,9-dione:

[1315] Diethylazodicarboxylate (1.24 ml; 7.87 mmol) is added dropwise atambient temperature and under an argon atmosphere to a solution inanhydrous DMF (30 ml) of (+)-EHHOPD (1.58 g; 7.08 mmol; Stage 80.c.),the product of Stage 81.c (1.62 g; 7.06 mmol) and tributylphosphine(1.91 ml; 7.87 mmol). The mixture thus obtained is then agitated for 16hours. The reaction medium is then evaporated to dryness under reducedpressure. The residue is purified by chromatography on a silica column(eluant: ethyl acetate). The solid obtained is taken up in diethylether,filtered and dried in order to produce the product in the title (1.56 g;51% yield) in the form of a whitish solid (M.p. 196° C.).

[1316] NMR ¹H (DMSO): 0.84 (t, 3H); 1.74 (m, 2H); 3.02 (d, 1H); 3.34 (d,1H); 5.29 (s, 2H); 5.31 (dd, 2H); 5.75 (s, 1H); 6.51 (d, 1H); 7.80 (d,1H); 8.03 (dd, 1H); 8.07 (s, 1H); 8.17 (dd, 1H).

[1317] IR (KBr): 875, 1057, 1360, 1507, 1574, 1647, 1749 cm⁻¹.

[1318] 81.e.(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1319] A mixture of the product of Stage 81.d (1.53 g; 3.52 mmol; Stage2.d.), tetrabutylammonium bromide (1.25 g; 3.87 mmol), potassium acetate(520 mg; 5.28 mmol), triphenylphosphine (180 mg; 0.70 mmol) andpalladium (II) acetate (79 mg; 0,35 mmol) is agitated under an argonatmosphere in anhydrous acetonitrile heated at reflux for 22 hours.After the reaction medium has returned to ambient temperature,concentration under reduced pressure is carried out beforechromatography on a silica column (eluant: CH₂Cl₂/MeOH mixture 98/2).The product in the title is then obtained (960 mg; yield 68%; puritydetermined by HPLC: 97.1%). This product is taken up in anhydrous CH₂Cl₂(100 ml) and agitation is carried out for 24 hours, followed byfiltering and drying under reduced pressure in order to produce thepurified product of the title (850 mg; yield 61%; purity determined byHPLC: 99.6%) in the form of a white solid.

[1320] NMR ¹H (DMSO): 0.87 (t, 3H); 1.85 (m, 2H); 3.08 (d, 1H); 3.44 (d,1H); 5.26 (s, 2H); 5.39 (d, 2H); 5.52 (d, 2H); 5.99 (wide peak, 1H);7.39 (s, 1H); 8.15 (dd, 1H); 8.23 (dd, 1H); 8.68 (s, 1H).

[1321] IR (KBr): 871, 1261, 1512, 1579, 1654, 1746 cm⁻¹.

Example 82(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]-4-methyl-hexahydropyridiniumchloride

[1322] 82.a. 1-(2-amino-4-chloro-5-methylphenyl)-2-chloro-ethanone

[1323] 3-chloro-4-methylaniline (44.4 ml; 0.366 mol) in1,2-dichloroethane (440 ml), under an argon atmosphere, is cooled downin an ice bath. The following are added dropwise and in the order ofthis mixture: boron trichloride (1M in heptane; 400 ml; 0.4 mol),chloroacetonitrile (28 ml; 0.44 mol) and diethylaluminium chloride (1Min heptane; 400 ml; 0.4 mol). For the addition, the temperature ismaintained below 20° C. The resultant mixture is then heated at refluxfor 3 hours, then cooled down to 10° C. The hydrolysis of the reactionmedium is then carried out cautiously using 2N hydrochloric acid (240ml) and it is heated at reflux for 1 hour. Water (1 l) and ethyl acetate(1 l) are added, the mixture obtained is agitated for 15 minutes beforeseparating the phases. The aqueous phase is again extracted with ethylacetate (200 ml), and the combined organic phases are washed with water(500 ml). After drying over magnesium sulphate the organic phase isconcentrated. The residue is taken up in petroleum ether (fractionhaving a boiling point of 45 to 60° C.; 150 ml) and the mixture thusobtained is left for 16 hours at 4° C. The resultant precipitate iscollected by filtration, washed with petroleum ether and dried underreduced pressure in order to produce the product in the title (25 g; 31%yield). M.p. 129-130° C.

[1324] NMR ¹H (DMSO): 2.20 (s, 3H); 4.98 (s, 2H); 6.90 (s, 1H); 7.15(wide peak, 2H); 7.70 (s, 1H).

[1325] IR (KBr): 871, 1018, 1183, 1225, 1270, 1533, 1577, 1619, 1662cm⁻¹.

[1326] 82.b. Ethyl7-chloro-4-chloromethyl-6-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate

[1327] The product of Stage 82.a (25 g; 0.11 mol) and triethylamine(30.6 ml; 0.22 mol) are mixed together in acetonitrile (520 ml).Ethylmalonyl chloride (28.1 ml; 0.22 mol) is added at ambienttemperature and under an argon atmosphere. The mixture obtained isagitated for 3 hours. Sodium ethanolate (prepared by the dissolution of3 g, i.e. 0.13 mol, of sodium in 140 ml of absolute ethanol) is thenadded dropwise and the resultant mixture is agitated at ambienttemperature for 16 hours. The precipitate is collected by filtration,washed successively with ethanol, water, ethanol and ether. It is thendried under reduced pressure at 70° C. over phosphorus pentoxide inorder to produce the product in the title (28.6 g; 83% yield) in theform of a whitish powder.

[1328] NMR ¹H (DMSO): 1.30 (t, 3H); 2.40 (s, 3H); 4.35 (q, 2H); 4.85 (s,2H); 7.41 (s, 1H); 7.91 (s, 1H); 12.15 (wide peak, 1H).

[1329] IR(KBr): 879, 1108, 1250, 1288, 1483, 1664, 1721 cm⁻¹.

[1330] 82.c. Ethyl2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate

[1331] The product of Stage 82.b (28.4 g; 90 mmol) is heated for 4 hoursat reflux in phosphorus oxychloride (400 ml). The mixture obtained isconcentrated under reduced pressure (20 mm Hg) at 80° C. The residue istaken up in diisopropylether (400 ml). The resultant precipitate iscollected by filtration, washed with ether and petroleum ether, thendried under reduced pressure in order to produce the product in thetitle (25.4 g; 85% yield) in the form of a whitish powder (M.p. 126-127°C.).

[1332] NMR ¹H (DMSO): 1.37 (t, 3H); 2.58 (s, 3H); 4.49 (q, 2H); 5.14 (s,2H); 8.16 (s, 1H); 8.35 (s, 1H).

[1333] IR(KBr): 874, 1006, 1163, 1243, 1278, 1577, 1723 cm⁻¹.

[1334] 82.d. 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolylmethanol

[1335] The product of Stage 82.c (25.2 g; 76.5 mmol) is mixed under anargon atmosphere with dichloroethane (630 ml). Diisobutylaluminiumhydride (1M in dichloromethane; 307 ml; 307 mmol) is added dropwisewhile the reaction mixture is agitated and the temperature is maintainedbelow 20° C. The reaction mixture is then agitated at ambienttemperature for 3 hours, then poured into an aqueous solution ofpotassium tartrate (concentrated to 20% by weight; 1.5 l). The emulsionthus obtained is agitated vigorously for 1 hour, filtered on celite andthe two phases are then separated. The aqueous phase is extracted withethyl acetate (200 ml) and the combined organic phases are washed withan aqueous solution of sodium chloride (concentrated to 20% by weight;500 ml). The organic phase obtained is dried over magnesium sulphate,filtered and concentrated under reduced pressure. The residue is takenup in diethylether (50 ml) and the resultant precipitate is collected byfiltration. By drying under reduced pressure, the product in the titleis obtained (18.3 g; 93% yield) in the form of a whitish powder (M.p.169-170° C.).

[1336] NMR ¹H (DMSO): 2.57 (t, 3H); 4.84 (s, 2H); 5.36 (s, 2H); 8.06 (s,1H); 8.27 (s, 1H)

[1337] IR(KBr): 870, 1022, 1102, 1304, 1482, 1567 cm⁻¹.

[1338] 82.e.2,7-dichloro-6-methyl-4-(4-methylpiperidinomethyl)-3-quinolylmethanol

[1339] A solution of the product of Stage 82.d (16.2 g; 55.7 mmol) inTHF (70 ml) is treated with a solution of 4-methylpiperidine (23 ml; 195mmol). The mixture obtained is agitated at ambient temperature for 2hours. Water (200 ml) and dichloroethane (200 ml) are added. The organicphase is washed with an aqueous solution of sodium chloride(concentrated to 20% by weight; 100 ml), dried over magnesium sulphateand concentrated under reduced pressure. By crystallization of theresidue from diethylether, the product in the title is obtained (18.3 g;93% yield) in the form of a white crystalline solid (M.p. 170-171,5°C.).

[1340] NMR ¹H (CDCl₃): 0.88 (d, 3H); 1.17 (m, 2H); 1.42 (m, 1H); 1.60(m, 2H); 2.19 (t, 2H); 2.56 (s, 3H); 2.82 (d, 2H); 4.02 (s, 2H); 4.93(s, 2H); 6.36 (wide peak, 1H); 7.95 (s, 1H); 8.02 (s, 1H).

[1341] IR (KBr): 971, 1013, 1105, 1293, 1479, 1559 cm⁻¹.

[1342] 82.f.(+)-8-[2,7-dichloro-6-methyl-4-(4-methylpiperidinomethyl)-3-quinolylmethyl]-5-ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pydidine-3,9-dione

[1343] A suspension of (+)-EHHOPD (obtained in Stage 80. c.; 1.56 g; 7,0mmol) in anhydrous dioxane (70 ml) is treated successively, under anargon atmosphere, with the product of Stage 82. e (2.47 g; 7.0 mmol),triphenylphosphine (2.02 g; 7.7 mmol) and diisopropyl azodicarboxylate(1.07 ml; 10.5 mmol). The mixture is agitated at ambient temperature for16 hours. The volatile substances are then evaporated off under reducedpressure. The residue is purified by chromatography on a silica column(eluant: ethyl acetate). The solid obtained is taken up in diethylether,filtered and dried in order to produce the product in the title (1.96 g;50% yield) in the form of a whitish solid (M.p. 182° C.).

[1344] NMR ¹H (DMSO): 0.89 (m, 8H); 1.23 (m, 1H); 1.41 (t, 2H); 1.64 (m,2H); 2.09 (q, 2H); 2.59 (m, 5H); 3.15 (dd, 2H); 4.06 (dd, 2H); 5.31 (dd,2H); 5.35 (dd, 2H) 5.75 (s, 1H); 6.29 (d, 1H); 7.17 (d, 1H); 8.06 (s,1H); 8.46 (s, 1H).

[1345] IR (KBr): 878, 1053, 1275, 1474, 1572, 1648, 1747 cm⁻¹.

[1346] 82.g.(+)-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-c]quinoline-3,15-dione

[1347] A mixture of the product of Stage 82.f (3.80 g; 6.80 mmol),tetrabutylammonium bromide (2.42 g; 7.5 mmol), potassium acetate (1.00g; 10.2 mmol), triphenylphosphine (890 mg; 3.4 mmol) and palladium (II)acetate (220 mg; 0,68 mmol) is agitated under an argon atmosphere inanhydrous acetonitrile (85 mg) at reflux for 24 hours. After coolingdown to ambient temperature, the resultant precipitate is collected byfiltration and washed successively with acetonitrile, water, acetone anddiethylether in order to produce, after drying under reduced pressure,the product in the title (2.5 g; 70% yield) in the form of a whitishpowder.

[1348] NMR ¹H (DMSO): 0.86 (m, 6H); 1.12 (q, 2H); 1.36 (m, 1H); 1.56 (d,2H); 1.84 (q, 2H); 2.12 (t, 2H); 2.56 (s, 3H); 2.83 (dd, 2H); 3.26 (dd,2H); 4.03 (dd, 2H); 5.28 (dd, 2H); 5.45 (dd, 2H); 6.04 (s, 1H); 7.34 (s,1H); 8.14 (s, 1H); 8.38 (s, 1H).

[1349] IR (KBr): 870, 1058, 1208, 1280, 1477, 1593, 1655, 1749 cm−¹.

[1350] 82.h. (+)1-[(5R)-9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-c]quinolin-12-ylmethyl]-4-methyl-hexahydropyridiniumchloride:

[1351] A mixture of the product of Stage 82. g (2.3 g; 7.7 mmol) andabsolute ethanol (300 ml) is subjected to ultrasound for 2 minutes. Themilky suspension obtained is agitated and treated with hydrochloric acid(1N solution; 13.2 ml; 13.2 mmol) in order to produce a light yellowsolution which, at rest, forms a gel-type precipitate. The precipitateis collected by filtration on a BŸchner and washed successively withethanol and ether, then dried under reduced pressure in order to producethe product in the title (2.1 g; 85% yield).

[1352] NMR ¹H (DMSO): 0.87 (m, 6H); 1.59 (m, 5H); 1.84 (q, 2H); 2.64 (s,3H); 3.28 (dd, 2H); 3.45 (s, 2H); 4.93 (s, 2H); 5.47 (dd, 2H); 5.61 (s,2H); 6.04 (wide peak, 1H); 7.41 (s, 1H); 8.28 (s, 1H); 8.63 (s, 1H);10.30 (wide peak, 1H).

[1353] IR (KBr): 1043, 1212, 1479, 1585, 1655, 1751 cm⁻¹.

Example 83(5R)-5-ethyl-11-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1354] Stage 83a.: quinidinium(3R)-3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoate

[1355] Tert-butyl3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoate (obtainedaccording to the method described in the Patent Application WO 97/00876;40 g; 100 mmol) is treated with trifluoroacetic acid (150 ml) and thereaction medium is agitated for 18 hours at 20° C., then concentratedunder reduced pressure. The residue, taken up in a saturated aqueoussolution of sodium bicarbonate (200 ml), is washed with dichloromethane(2×100 ml) and the resulting solution is acidified to pH=1 with 6 Nhydrochloric acid, then extracted with dichloromethane (2×200 ml). Thecombined extracts are dried over magnesium sulphate and concentrated.The solution is dried over magnesium sulphate and concentrated. Theracemic acid thus obtained (31.1 g; 90 mmol), taken up in isopropylalcohol (30 ml), is treated with a quinidine solution (29.2 g; 90 mmol)in isopropyl alcohol (30 ml), and the resulting mixture is agitated at50° C. until complete dissolution. The temperature is allowed to reduceto 40° C., the agitation is stopped and the reaction medium allowed tocool down to ambient temperature. The medium is taken to 0° C. withoutagitation then maintained at this temperature for 16 hours. Then thetemperature is allowed to rise to 20° C. and agitation is carried outuntil crystallization. The medium is diluted with isopropyl alcohol thenfiltered. The precipitate is rinsed with isopropyl alcohol. Thedextrorotatory salt precipitates whilst the levorotatory salt remains insolution in isopropyl alcohol. The filtrate is recovered which isconcentrated to produce the expected product. Analysis by HPLC (columnCHIRAL-AGP 5 μ (10 cm×4 mm) eluted with an isopropyl alcohol/water/phosphate buffer mixture pH 6.5 30/920/50, at a flow rate of 1.2 ml/min,UV detection at 280 nm) shows retention times of 6.4 min for thelevorotatory salt and 2.8 min for the dextrorotatory salt and adiastereoisomeric ratio of 83/17.

[1356] Stage 83b:(5R)-5-ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxepino[3,4-c]pyridin-3,9-dione,or (+)-EHHOPD

[1357] The residue obtained in Stage 83a is agitated for 16 hours at 20°C. in a mixture of dichloromethane (270 ml) and 1N hydrochloric acid(270 ml). After decanting, the organic phase is concentrated, and theresidue is taken up in methanol (87 ml) to be used in the followingphase. This solution is poured under nitrogen onto Palladium at 10% ondamp carbon at 50% (27.7 g; 13 mmol). The reaction medium is agitatedfor 5 min, then poured into a solution of ammonium formate (11.5 g; 183mmol) in methanol (135 ml). The reaction medium is agitated for 30 minwhilst allowing the temperature to rise, then it is heated at 40° C. for30 min. The medium is then filtered on a bed of Clarcel andconcentrated. Toluene (40 ml) is poured in followed by evaporation, andthis operation is repeated in order to eliminate the traces of methanol.The residue, taken up in tetrahydrofuran (45 ml), is treated with asolution of dicyclohexylcarbodiimide (7.18 g; 34.5 mmol) intetrahydrofuran (20 ml). The reaction medium is heated at 50° C. for 1hour, then taken to 20° C., and the dicyclohexylurea is filtered. Thefiltrate is concentrated to dryness and the residue, taken up inacetonitrile (46 ml), is treated with sodium iodide (6.0 g; 40.5 mmol)and trimethylsilyl chloride (5.13 ml; 40.5 mmol). The reaction medium ismaintained under agitation at ambient temperature for 5 hours, thenacetonitrile (28 ml) and water (5.6 ml) are added. The precipitateobtained is recovered by filtration, then taken up in water (10 ml), andthe mixture obtained is neutralized using a solution of ammoniumhydroxide. The precipitate is recovered by filtration then taken up inacetone (40 ml) to which water (150 ml) is added. The crystals formedare recovered by filtration and dried to produce 3 g of (+)-EHHOPD withan enantiomeric proportion of 99.4/0.6.

[1358] NMR ¹H (DMSO-d6, δ): 0.8 (t, 3H); 1.65 (m, 2H); 3.00-3.35 (q,2H); 5.3 (q, 2H); 5.7 (s, 1H); 6.35 (d, 1H); 7.3 (d, 1H); 11.7 (s, 1H).

[1359] Stage 83c: 2-amino-6-fluorophenylmethanol

[1360] A solution under argon of 2-amino-6-fluorobenzoic acid (5 g; 32mmol) in anhydrous tetrahydrofuran (100 ml) is treated with lithiumaluminium hydride (1M in tetrahydrofuran; 64 ml; 64 mmol) at ambienttemperature. The reaction medium is agitated for 3 hours, thenhydrolyzed at 0° C. with a saturated aqueous solution of ammoniumchloride (100 ml). The resulting mixture is extracted with ethyl acetate(2×70 ml). The combined extracts are washed with water and with asaturated aqueous solution of sodium chloride, then dried over magnesiumsulphate and concentrated to produce 3.8 g of the desired product, awhite solid (m.p.: 93° C.).

[1361] IR (KBr): 784, 1001, 1471, 1591, 1621 cm⁻¹.

[1362] NMR ¹H (DMSO-d6, δ): 4.44 (dd, 2H); 4.93 (t, 1H); 5.27 (s, 2H);6.27 (t, 1H); 6.45 (d, 1H); 6.96 (q, 1H).

[1363] Stage 83d:=ethyl 2-(3-fluoro-2-hydroxymethylphenylcarbamoyl)acetate

[1364] A solution of aminobenzyl alcohol (obtained in Stage 83c; 3.8 g;27 mmol) and imidazole (4.3 g; 64 mmol) in N,N-dimethylformamide (52 ml)is treated with tert-butyldiphenylsilyl chloride (8.37 ml; 32 mmol). Theresulting mixture is agitated for 2 hours at ambient temperature, thenwater (100 ml) is added, followed by extraction with ethyl acetate (2×60ml). The combined extracts are washed with water and with a saturatedaqueous solution of sodium chloride, then dried over magnesium sulphateand concentrated. The silylated intermediate thus obtained (10 g) istaken up in acetonitrile (52 ml), then triethylamine (4.5 ml; 32.4 mmol)is added to the solution, and the resulting mixture is treated dropwisewith ethylmalonyl chloride (4.15 ml; 32.4 mmol). The resulting mixtureis agitated for 2 hours at ambient temperature, then water (100 ml) isadded, followed by extraction with ethyl acetate (2×60 ml). The combinedextracts are washed with water and with a saturated aqueous solution ofsodium chloride, then dried over magnesium sulphate and concentrated.The residue (16 g) is taken up in tetrahydrofuran (50 ml) and treateddropwise with tetrabutylammonium fluoride (1M in tetrahydrofuran; 27 ml;27 mmol). The resulting mixture is agitated for 1 hour at ambienttemperature, then water (100 ml) is added followed by extraction withethyl acetate (2×60 ml). The combined extracts are washed with water andwith a saturated solution of sodium chloride, then dried over magnesiumsulphate and concentrated. Purification of the residue by chromatographyat medium pressure (SiO₂, CH₂Cl₂/MeOH, 95/5) yields 4.8 g of a whitesolid (m.p.: 91° C).

[1365] IR (KBr): 1472, 1542, 1589, 1657, 1719, 3286, 3482 cm⁻¹.

[1366] NMR ¹H (DMSO-d6, δ): 1.19 (t, 3H); 3.54 (s, 2H); 4.14 (q, 2H);4.55 (dd, 2H); 5.21 (t, 1H); 6.97 (t, 1H); 7.31 (dd, 1H); 7.53 (d, 1H).

[1367] Stage 83e: ethyl5-fluoro-2-oxo-1,2-dihydro-3-quinolinecarboxylate

[1368] A solution of malonic derivative (obtained in Stage 83d; 4.8 g;19 mmol) in dichloromethane (280 ml) is treated with pyridiniumdichromate (8.3 g; 22 mmol). The resulting suspension is agitated for 4hours at ambient temperature, then treated with triethylamine (30 ml;220 mmol). The reaction medium is agitated at ambient temperature for 16hours, then concentrated under reduced pressure. Purification of theresidue by chromatography at medium pressure (SiO₂, CH₂Cl₂/MeOH, 95/5)yields 2.1 g of a yellow solid (m.p.: 180° C.).

[1369] IR (KBr): 1441, 1498, 1655, 1747 cm⁻¹.

[1370] NMR ¹H (DMSO-d6, δ): 1.31 (t, 3H); 4.28 (q, 2H); 7.06 (t, 1H);7.16 (d, 1H); 7.61 (dd, 1H); 8.43 (s, 1H); 12.27 (s, 1H).

[1371] Stage 83f: ethyl 2-chloro-5-fluoro-3-quinolinecarboxylate

[1372] The quinolone (obtained in Stage 83e; 2.1 g) is heated at 80° C.in phosphorus oxychloride (14 ml) until the reaction is complete (TLCcontrol : SiO₂, CH₂Cl₂/MeOH, 95/5). The resulting solution is thenconcentrated under reduced pressure and the residue is taken up inwater. The precipitate thus formed is recovered by filtration, washedwith water until the pH is neutral, and dried under reduced pressure inthe presence of phosphorus pentoxide to produce 1.8 g of a white solid(m.p.: 97° C.).

[1373] IR (KBr): 1268, 1631, 1723 cm⁻¹.

[1374] NMR ¹H (DMSO-d6, δ): 1.38 (t, 3H); 4.42 (q, 2H); 7.60 (t, 1H);7.89 (d, 1H); 7.97 (dd, 1H); 8.92 (s, 1H).

[1375] Stage 83g: 2-chloro-5-fluoro-3-quinolylmethanol

[1376] A solution of quinolinecarboxylate (obtained in Stage 83f; 1.8 g;6.7 mmol) in dichloromethane (40 ml) under argon is treated dropwisewith diisobutylaluminium hydride (1M in dichloromethane; 20 ml; 20 mmol)at ambient temperature maintained at 10° C. by an ice-cooled water bath.The reaction mixture is agitated for 1 hour at ambient temperature, thenpoured onto a solution of sodium and potassium tartrate at 20% (200 ml).The resulting mixture is agitated vigorously for 1 hour, then filteredon celite. The filtrate is extracted with dichloromethane (2×100 ml).The combined extracts are washed with water and with a saturatedsolution of sodium chloride, then dried over magnesium sulphate andconcentrated. Purification of the residue by chromatography at mediumpressure (SiO₂, CH₂Cl₂/MeOH, 98/2) yields 450 mg of a white solid (m.p.:176° C.).

[1377] NMR ¹H (DMSO-d6, δ): 4.71 (d, 2H); 5.78 (t, 3H); 7.51 (t, 1H);7.75-7.83 (m, 2H); 8.50 (s, 1H).

[1378] Stage 83h:(5R)-5-ethyl-11-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-]quinoline-3,15-dione

[1379] A solution of quinolylmethanol (obtained in Stage 83 g; 422 mg; 2mmol), of (+)-EHHOPD (obtained in Stage 1b; 446 mg; 2 mmol) andtriphenylphosphine (592 mg; 2.2 mmol) in N,N-dimethylformamide (8 ml) istreated dropwise with isopropyl azodicarboxylate (0.43 ml; 2.2 mmol).The reaction mixture is agitated for 16 h at ambient temperature, thenwater (100 ml) is added, followed by extraction with ethyl acetate(2×100 ml). The combined extracts are washed with water and with asaturated solution of sodium chloride, then dried over magnesiumsulphate and concentrated under reduced pressure. The residue ispurified by chromatography at medium pressure (SiO₂, AcOEt/heptane,30/70). A mixture under argon of the intermediate obtained (325 mg; 0.78mmol), triphenylphosphine (42 mg; 0.156 mmol), potassium acetate (114mg; 1.17 mmol), tetrabutylammonium bromide (276 mg; 0.86 mmol) andpalladium acetate (0.078 mmol) is taken to reflux in anhydrousacetonitrile for 16 hours, then cooled down to ambient temperature andconcentrated under reduced pressure. The residue is purified bychromatography at medium pressure (SiO₂, MeOH/CH₂Cl₂, 5/95) to produce80 mg of the expected solid (m.p.>250° C.).

[1380] IR (KBr): 1659, 1734, 3386 cm⁻¹.

[1381] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H);3.46 (d, 1H); 5.28 (s, 2H); 5.39 (d, 1H); 5.52 (d, 1H); 6.02 (s, 1H);7.43 (s, 1H); 7.55 (t, 1H); 7.85 (q, 1H); 8.01 (d, 1H); 8.82 (s, 1H).

Example 84(5R)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1382] This compound is obtained by applying Stages 83c to 83h of theoperating method of Example 83 above to 2-amino-4-fluorobenzoic acid. Asolid (m.p.>250° C.) is obtained.

[1383] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 1.84 (q, 2H); 3.04 (d, 1H);3.47 (d, 1H); 5.24 (s, 2H); 5.39 (d, 1H); 5.52 (d, 1H); 6.06 (s, 1H);7.39 (s, 1H); 7.65 (t, 1H); 7.88 (d, 1H); 8.22 (dd, 1H); 8.71 (s, 1H).

Example 85(5R)-5-ethyl-8-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1384] This compound is obtained by applying Stages 83c to 83h of theoperating method of Example 83 above to 2-amino-3-fluorobenzoic acid(prepared according to Muchowski, et al., J. Org. Chem., vol. 45, p.4798). A solid (m.p.>250° C.) is obtained.

[1385] IR (KBr): 1659, 1731, 3344 cm⁻¹.

[1386] NMR ¹H (DMSO-d6, δ): 0.88 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H);3.47 (d, 1H); 5.29 (s, 2H); 5.40 (d, 1H); 5.53 (d, 1H); 6.06 (s, 1H);7.44 (s, 1H); 7.69 (m, 2H); 7.96 (m, 1H); 8.75 (s, 1H).

Example 86(5R)-12-benzyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1387] Stage 86a: 1-(2-aminophenyl)-2-phenyl-1-ethanone.

[1388] A solution of 2-aminobenzonitrile (4.25 g, 36 mmol) in anhydrousdiethyl ether (40 ml) at 0° C. is treated under argon withbenzylmagnesium chloride (2M in tetrahydrofuran; 50 ml; 100 mmol). Thereaction medium is maintained under agitation for 1 hour at ambienttemperature, then hydrolyzed at 0° C. by adding hydrochloric acid at10%, agitated for 1 hour, and neutralized with soda. The resultingmixture is extracted with ethyl acetate. The combined extracts arewashed with water and with a saturated solution of sodium chloride, thendried over magnesium sulphate and concentrated to produce 3.5 g of thedesired product, in the form of a white solid (m.p.: 100-101° C).

[1389] IR (KBr): 1469, 1612, 1725 cm⁻¹

[1390] NMR ¹H (DMSO-d6, δ): 4.25 (s, 2H); 6.53 (t, 1H); 6.74 (d, 1H);7,2-7.35 (m, 8H); 7.90 (d, 1H).

[1391] Stage 86b: ethyl4-benzyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate

[1392] A solution of amino-ketone (obtained in Stage 86a; 13.5 g; 16mmol) and triethylamine (3.9 ml, 28 mmol) in acetonitrile (66 ml) istreated at 10° C. dropwise with ethylmalonyl chloride (3.64 ml; 28mmol). The reaction medium is agitated for 16 hours at ambienttemperature, then treated with sodium ethoxide, obtained by dissolutionof sodium (0.4 g; 17 mmol) in ethanol (25 ml). The resulting mixture isagitated for 16 hours at ambient temperature, then water is added (200ml), followed by extraction with dichloromethane (2×100 ml). Thecombined extracts are washed with water and with a saturated solution ofsodium chloride, then dried over magnesium sulphate and concentrated.The residue is taken up in ethyl ether to produce a precipitate which isrecovered by filtration, dried under reduced pressure at 50° C., toproduce the expected solid (m.p.: 230° C.).

[1393] NMR ¹H (DMSO-d6, δ): 1.19 (t, 3H); 4.17 (s, 2H); 4.27 (q, 2H);7.13 (t, 1H); 7.15-7.20 (m, 1H); 7.20-7.40 (m, 5H); 7.49 (t, 1H); 7.69(d, 1H); 12.15 (s, 1H).

[1394] Stage 86c:(5R)-12-benzyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1395] Stages 86f to 86h of the operating method of Example 86 above areapplied to the quinolone obtained according to Stage 86b. A solid isobtained (m.p.>250° C.).

[1396] IR (KBr): 1578, 1655, 1751 cm⁻¹.

[1397] NMR ¹H (DMSO-d6, δ): 0.87 (t, 3H); 1.87 (q, 2H); 3.05 (d, 1H);03.49 (d, 1H); 4.65 (d, 1H); 4.70 (d, 1H); 5.20 (d, 1H); 5.25 (d, 1H);5.39 (d, 1H); 5.52 (d. 1H); 6.06 (s, 1H); 7.15-7.30 (m, 5H); 7.41 (s,1H); 7.67 (t, 1H); 7.83 (t, 1H); 8.16 (d, 1H); 8.28 (d, 1H).

Example 87(5R)-12-butyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1398] 2-aminobenzonitrile is treated with n-butylmagnesium bromideaccording to a procedure similar to Stage 86a and the resultingamino-ketone is treated according to a procedure similar to Stage 86b.Stages 83f to 83h of the operating method of Example 83 above areapplied to the quinolone obtained. A solid is obtained (m.p. 220-221°C.).

[1399] IR (KBr): 1611; 1655; 1725 cm⁻¹.

[1400] NMR ¹H (DMSO-d6, δ): 0.87 (t, 3H); 0.96 (t, 3H); 1.49 (q, 2H);1.67 (q, 2H); 1.86 (q, 2H); 3.05 (d, 1H); 3.19 (t, 2H); 3.49 (d, 1H);5.28 (s, 2H); 5.40 (d, 1H); 5.54 (d, 1H); 6.05 (s, 1H); 7.39 (s, 1H);7.72 (t, 1H); 7.85 (t, 1H); 8.14 (d, 1H); 8.26 (d, 1H).

Example 88(5R)-5,12-diethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1401] 2-aminobenzonitrile is treated with ethylmagnesium bromideaccording to a procedure similar to Stage 86a and the resultingamino-ketone is treated according to a procedure similar to Stage 86b.Stages 83f to 83h of the operating method of Example 83 above areapplied to the quinolone obtained. A solid is obtained (m.p.>280° C.).

[1402] IR (KBr): 1652, 1758, 3329 cm⁻¹.

[1403] NMR ¹H (DMSO-d6, δ): 0.85 (t, 3H); 1.31 (t, 3H); 1.87 (q, 2H);3.04 (d, 1H); 3.24 (q, 2H); 3.54 (d, 1H); 5.25 (s, 2H); 5.36 (d, 1H);5.53 (d, 1H); 6.06 (s, 1H); 7.39 (s, 1H); 7.72 (t, 1H); 7.85 (t, 1H);8.15 (d, 1H); 8.28 (d, 1H).

Example 89(5R)-5-ethyl-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1404] 2-aminophenyl-phenylmethanone is treated according to a proceduresimilar to Stage 86b. Stages 83f to 83h of the operating method ofExample 83 are applied to the quinolone obtained. A solid is obtained(m.p.>250° C.).

[1405] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H);3.49 (d, 1H); 5.09 (s, 2H); 5.38 (d, 1H); 5.50 (d, 1H); 6.07 (s, 1H);7.45 (s, 1H); 7.60-7.75 (m, 6H); 7.82 (d, 1H); 7.90 (t, 1H); 8.25 (d,1H).

Example 90(5R)-12-cyclohexyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1406] 2-aminobenzonitrile is treated with cyclohexylmagnesium chlorideaccording to a procedure similar to Stage 86a and the resultingamino-ketone is treated according to a procedure similar to that ofStage 86b. Stages 86f to 86h of the operating method of Example 86 aboveare applied to the quinolone obtained. A solid is obtained (m.p.>250°C.).

[1407] IR (KBr): 1655, 1728, 3500 cm⁻¹.

[1408] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 1.42 (t, 1H); 1.59 (t, 2H);1.84 (m, 9H); 3.04 (d, 1H); 3.48 (d, 1H); 3.69 (m, 1H); 5.39 (d, 1H);5.40 (s, 2H); 5.53 (d, 1H); 6.06 (s, 1H); 7.38 (s, 1H); 7.70 (t, 1H);7.83 (t, 1H); 8.13 (d, 1H); 8.37 (s, 1H).

Example 91(5R)-5-ethyl-5-hydroxy-12-(4-methylphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione2-aminophenyl-4-methylphenylmethanone is treated according to aprocedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained. Asolid is obtained (m.p.>280° C.).

[1409] IR (KBr): 1655, 1754, 3407 cm⁻¹.

[1410] NMR ¹H (DMSO-d6, δ): 0.87 (t, 3H); 1.87 (q, 2H); 2.47 (s, 3H);3.07 (d, 1H); 3.48 (d, 1H); 5.07 (d, 2H); 5.39 (d, 1H); 5.49 (d, 1H);6.04 (s, 1H); 7.45 (s, 1H); 7.48 (m, 2H); 7.54 (m, 2H); 7.65 (m, 1H);7.85 (m, 2H); 8.22 (d, 1H).

Example 92(5R)-10-chloro-5-ethyl-12-(2-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1411] 2-amino-5-chlorophenyl-2-fluorophenylmethanone is treatedaccording to a procedure similar to that of Stage 86b. Stages 83f to 83hof the operating method of Example 83 above are applied to the quinoloneobtained. A solid is obtained (m.p.>250° C.).

[1412] IR (KBr): 1656, 1744, 3397 cm⁻¹.

[1413] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 1.85 (q, 2H); 3.06 (d, 1H);3.47 (d, 1H); 4.93 (d, 1H); 5.17 (d, 1H); 5.37 (d, 1H); 5.49 (d, 1H);6.05 (s, 1H); 7.46 (s, 1H); 7.50-7.65 (m, 3H); 7.65-7.80 (m, 2H); 7.91(d, 1H); 8.27 (d, 1H).

Example 93(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1414] Stage 93a: 6,7-difluoro-2-phenyl-4H-benzo[d][3.1]oxazine-4-one

[1415] A mixture of 2-amino-4,5-difluorobenzoic acid (3.46 g; 20 mmol)and benzoyl chloride (56 ml; 480 mmol) is taken to reflux for 16 hours,then poured into a saturated aqueous solution of sodium bicarbonate (200ml) and agitated at 80° C. for 2 hours. The resulting mixture isextracted with dichloromethane (2×100 ml). The combined extracts arewashed with water and with a saturated solution of sodium chloride, thendried over magnesium sulphate and concentrated under reduced pressure.The residue is taken up in ethyl ether and the precipitate thus formedis recovered by filtration, washed with ethyl ether, and dried underreduced pressure to produce 3.2 g of a white solid (m.p.: 154° C.).

[1416] IR (KBr): 1613, 1657, 3341, 3467 cm⁻¹.

[1417] NMR ¹H (DMSO-d6, δ): 7.5-7.8 (m, 3H); 7.8-7.9 (m, 1H); 8.1-8.3(m, 1H).

[1418] Stage 93b: 2-benzoyl-4,5-difluoro-1-phenylcarboxamidobenzene

[1419] A suspension of benzoxazine (obtained according to Stage 93a;6.78 g; 26 mmol) in dichloromethane (260 ml) is treated dropwise underargon at −78° C. with phenylmagnesium bromide (3M in ethyl ether; 22 ml;66 mmol). The resulting mixture is agitated at −78° C. for 1 hour, thenhydrolyzed by adding a saturated aqueous solution of ammonium chloride(200 ml) and extracted with dichloromethane (2×100 ml). The combinedextracts are washed with water and with a saturated solution of sodiumchloride, then dried over magnesium sulphate and concentrated underreduced pressure. The residue taken up in isopropyl ether produceswhites crystals which are recovered by filtration and dried. 7.3 g ofproduct is obtained (m.p.: 58-59° C.).

[1420] IR (KBr): 1423, 1537, 1599, 1682 cm⁻¹.

[1421] NMR ¹H (DMSO-d6, δ): 7.4-7.6 (m, 9H); 7.69 (d, 2H); 7.88 (dd,1H).

[1422] Stage 93c: 2-amino-4,5-difluorophenyl-phenylmethanone

[1423] A solution of N-benzoylated amino-ketone (obtained according toStage 93b; 7.3 g; 21.7 mmol) in glacial acetic acid (300 ml) is treatedwith hydrobromic acid at 48% (150 ml) and the reaction medium is takento reflux for 10 hours. After cooling down to ambient temperature, theresulting mixture is concentrated under reduced pressure, then taken upin a saturated aqueous solution of sodium bicarbonate (200 ml) andextracted with ethyl acetate (2×100 ml). The combined extracts arewashed with water and with a saturated solution of sodium chloride, thendried over magnesium sulphate and concentrated under reduced pressure.The residue is taken up with pentane and the precipitate thus formed isrecovered by filtration to produces 4 g of a light yellow solid (m.p.:100-101° C.).

[1424] IR (KBr): 1514, 1563, 1645, 3372, 3482 cm ¹.

[1425] NMR ¹H (DMSO-d6, δ): 6.83 (dd, 1H); 7.1-7.4 (m, 3H); 7.5-7.7 (m,5H).

[1426] Stage 93d:(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1427] The aminoketone obtained in Stage 93c is treated according to aprocedure similar to that of Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained. A solid is obtained (m.p.>250° C.).

[1428] IR (KBr): 1659, 1734, 3386 cm⁻¹.

[1429] NMR ¹H (DMSO-d6, δ): 0.85 (t, 3H); 1.80 (q, 2H); 3.06 (d, 1H);3.45 (d, 1H) 5.00 (d, 1H); 5.35 (d, 1H); 5.48 (d, 1H); 6.03 (s, 1H);7.39 (s, 1H); 7.55-7.75 (m, 6H); 8.24 (dd, 1H).

Example 94(5R)-5-ethyl-9-fluoro-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1430] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c and the resulting aminoketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained. A solid is obtained (m.p.>250° C.).

[1431] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 1.84 (q, 2H); 3.06 (d, 1H);3.46 (d, 1H) 5.00 (d, 1H); 5.08 (d, 1H); 5.37 (d, 1H); 5.49 (d, 1H);6.03 (s, 1H); 7.43 (s, 1H); 7.50-7.80 (m, 6H); 7.85 (t, 1H); 7.96 (d,1H).

Example 95(5R)-12-butyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1432] Stage 95a: N-(3,4-difluorophenyl)acetamide

[1433] A mixture of 3,4-difluoroaniline (50 ml; 500 mmol) andtriethylamine (70 ml; 500 mmol) in dichloromethane (1.5l) is cooled downusing an ice bath. Acetic anhydride (71.5 ml; 750 mmol) is addeddropwise and the reaction mixture is agitated for 1 hour at ambienttemperature. The mixture obtained is then washed sequentially withwater, with a solution of sodium bicarbonate at 10%, and with asaturated solution of sodium chloride. The organic fraction, dried oversodium sulphate, is concentrated under reduced pressure. The residue issuspended in pentane, filtered and dried under reduced pressure in orderto produce the expected anilide, a beige solid (m.p.: 126-127.5° C.).

[1434] NMR ¹H (DMSO-d6, δ): 2.15 (s, 3H); 7,10-7.65 (m, 2H); 7,65-8.10(m, 1H); 10.30 (broad peak, 1H).

[1435] Stage 95b: 2-chloro-6,7-difluoro-3-quinolinecarbaldehyde

[1436] The acetanilide obtained according to Stage 95a (32 g; 220 mmol)is added to a Vilsmeyer's reagent obtained under argon with anhydrousN,N-dimethylformamide (34 ml; 440 mmol) cooled down using an ice bath,treated dropwise with phosphorus oxychloride (103 ml; 1.1 mol), thenagitated for 0.5 hours before allowing the temperature to rise toambient temperature. The mixture thus obtained is agitated at 70° C. for16 hours, then cooled down to ambient temperature. The reaction mediumis then poured dropwise into a water-ice mixture (400 ml), and theresulting mixture is agitated for 2 hours. The precipitate obtained isfiltered and washed with water until the pH is neutral, then dried underreduced pressure in the presence of phosphorus pentoxide in order toproduce a yellow solid (m.p.: 226-229° C).

[1437] IR (KBr): 888, 1061, 1262, 1507, 1691 cm⁻¹.

[1438] NMR ¹H (DMSO-d6, δ): 8.17 (dd, 1H); 8.39 (dd, 1H); 8.97 (d, 1H);10.34 (d, 1H).

[1439] Stage 95c: 2-chloro-6,7-difluoro-3-quinolylmethanol

[1440] A suspension of quinoline-carbaldehyde obtained according toStage 95b (9 g; 39 mmol) in methanol (400 ml) is treated with sodiumborohydride (2 g; 53 mmol) at ambient temperature for 0.5 h. The excessborohydride is destroyed by acetic acid (2 ml) and the reaction mediumis concentrated under reduced pressure. The residue, taken up in ethylacetate (500 ml), is washed sequentially with an aqueous solution ofsodium bicarbonate at 10%, with water, and with a saturated aqueoussolution of sodium chloride. The organic phase, dried over magnesiumsulphate, is concentrated under reduced pressure. The residue isrecrystallized from 1,2-dichloroethane in order to produce the expectedquinolylmethanol, a beige solid (m.p.: 166.5-167° C.).

[1441] IR (KBr): 871, 1038, 1253, 1513 cm⁻¹.

[1442] NMR ¹H (DMSO-d6, δ): 4.67 (d, 2H); 5.80 (t, 1H); 8.01 (dd, 1H);8.22 (dd, 1H) 8.48 (s, 1H).

[1443] Stage 95d:(5R)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1444] The quinolylmethanol obtained in Stage 95c is treated with(+)-EHHOPD according to the procedure in Stage 83h. A white solid isobtained.

[1445] IR (KBr): 871, 1261, 1512, 1579, 1654, 1746 cm⁻¹.

[1446] NMR ¹H (DMSO-d6, δ): 0.87 (t, 3H); 1.85 (m, 2H); 3.08 (d, 1H);3.44 (d, 1H); 5.26 (s, 2H); 5.39 (d, 2H); 5.52 (d, 1H); 5.99 (s, 1H);7.39 (s, 1H); 8.15 (dd, 1H); 8.23 (dd, 1H); 8.68 (s, 1H).

[1447] Stage 95e:(5R)-12-butyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1448] The product of Stage 95d (100 mg; 0.25 mmol) is dissolved in amixture of water (1.33 ml) and sulphuric acid at 95% (1 ml).Heptahydrated iron (III) sulphate (28 mg; 0.10 mmol); valeraldehyde(0.17 ml; 1.60 mmol) are added to this solution and the resultingsolution is cooled down with an ice bath. The reaction medium is thentreated dropwise with hydrogen peroxide at 30% (0.38 ml; 1 mmol);agitated for 5 hours at ambient temperature, then diluted with water (50ml) and extracted with dichloromethane (4×50 ml). The combined extractsare washed with water and with a saturated aqueous solution of sodiumchloride, then dried over magnesium sulphate and concentrated underreduced pressure. The residue is purified by chromatography at mediumpressure (SiO₂, MeOH/CH₂Cl₂, 5/95) in order to produce the expectedsolid (m.p.>275° C.).

[1449] IR (KBr): 1656, 1748, 3385 cm⁻¹.

[1450] NMR ¹H (DMSO-d6, δ): 0.85 (t, 3H); 0.94 (t, 3H); 1.47 (q, 2H);1.64 (m, 2H); 1.83 (q, 2H); 3.05 (d, 1H); 3.16 (m, 2H); 3.47 (d, 1H);5.27 (s, 2H); 5.39 (d, 1H); 5.52 (d, 1H); 6.05 (s, 1H); 7.35 (s, 1H);8.13 (m, 1H); 8.32 (m, 1H).

Example 96(5R)-12-benzyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1451] The product of Stage 95d is treated with phenylacetaldehydeaccording to a procedure similar to that of Stage 95e in order toproduce the expected solid (m.p. 275° C. (dec.)).

[1452] IR (KBr): 1656, 1707, 1749 cm⁻¹.

[1453] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 1.84 (q, 2H); 3.05 (d, 1H);3.48 (d, 1H); 4.64 (s, 2H); 5.19 (d, 2H); 5.38 (d, 1H); 5.51 (d, 1H);6.06 (s, 1H); 7.20 (m, 1H); 7.26 (m, 4H); 7.37 (s, 1H); 8.15 (t, 1H);8.31 (t, 1H).

Example 97(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1454] The product of Stage 95d is treated with butyraldehyde accordingto a procedure similar to that of Stage 95e in order to produce theexpected solid (m.p. 250° C.).

[1455] IR (KBr): 1656, 3425 cm⁻¹.

[1456] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 1.04 (t, 3H); 1.70 (q, 2H);1.84 (q, 2H); 3.07 (d, 1H); 3.15 (t, 2H); 3.46 (d, 1H); 5.25 (s, 1H);5.39 (d, 1H); 5.52 (d, 1H); 6.02 (s, 1H); 7.36 (s, 1H); 8.12 (m, 1H);8.34 (m, 1H).

Example 98(5R)-5,12-diethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1457] The product of Stage 95d is treated with propionaldehydeaccording to a procedure similar to that in Stage 95e in order toproduce the expected solid (m.p.>275° C.).

[1458] IR (KBr): 1656, 1725, 3308 cm⁻¹.

[1459] NMR ¹H (DMSO-d6, δ): 0.85 (t, 3H); 1.28 (t, 3H); 1.83 (q, 2H);3.05 (d, 1H); 3.19 (q, 2H); 3.47 (d, 1H); 5.29 (s, 2H); 5.39 (d, 1H);5.52 (d, 1H); 6.06 (s, 1H); 7.36 (s, 1H); 8.15 (m, 1H); 8.35 (m, 1H).

Example 99 (5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2-trimethylsilylethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1460] The product of Stage 95d is treated with 3-trimethylsilylpropanal(obtained according to Sarkar, T. K., et al., Tetrahedron (1990), vol.46, p. 1885) according to a procedure similar to Stage 95e in order toproduce the expected solid (m.p. 276° C.).

[1461] NMR ¹H (DMSO-d6, δ): 0.14 (s, 9H); 0.86 (m, 5H); 1.83 (q, 2H);3.07 (m, 3H); 3.46 (d, 1H); 5.26 (s, 2H); 5.40 (d, 1H); 5.51 (d, 1H);6.06 (s, 1H); 7.34 (s, 1H); 8.14 (m, 2H).

Example 100(5R)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1462] The operation is carried out with 3,5-difluoroaniline accordingto Stages 95a to 95c and the quinolylmethanol thus obtained is treatedwith (+)-EHHOPD according to the procedure of Stage 83h. A white solidis obtained (m.p. 227° C. (dec.)).

[1463] IR (KBr): 1638, 1748, 3310 cm⁻¹.

[1464] NMR ¹H (DMSO-d6, δ): 0.87 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H);3.46 (d, 1H); 5.26 (s, 2H); 5.40 (d, 1H); 5.52 (d, 1H); 6.03 (s, 1H);7.42 (s, 1H); 7.70 (t, 1H); 7.80 (d, 1H); 8.82 (s, 1H).

Example 101(5R)-12-butyl-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1465] The product of Example 100 is treated with valeraldehydeaccording to a procedure similar to that of Stage 95e in order toproduce the expected solid (m.p. 190° C.).

[1466] IR (KBr): 1657, 1751, 3385 cm⁻¹.

[1467] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 0.96 (t, 3H); 1.49 (q, 2H);1.66 (q, 2H); 1.84 (q, 2H); 3.07 (d, 1H); 3.46 (d, 1H); 5.30 (s, 2H);5.40 (d, 1 H); 5.53 (d, 1H); 6.03 (s, 1H); 7.39 (s, 1H); 7.67 (t, 1H);7.78 (d, 1H).

Example 102 (5R)-5,12-diethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1468] The product of Example 100 is treated with propionaldehydeaccording to a procedure similar to that in Stage 95e to produce theexpected solid (m.p. 255° C.).

[1469] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 1.33 (t, 3H); 1.84 (q, 2H);3.06 (d, 1H); 3.29 (m, 2H); 3.57 (d, 1H); 5.28 (s, 2H); 5.35 (d, 1H);5.53 (d, 1H); 6.04 (s, 1H); 7.38 (s, 1H); 7.69 (m, 1H); 7.80 (m, 1H).

Example 103(5R)-5-ethyl-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1470](5R)-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(obtained according to the procedure described in the PCT PatentApplication WO 97/00876) is treated with butyraldehyde according to aprocedure similar to that of Stage 95e in order to produce the expectedsolid (m.p. 265° C. (dec.)).

[1471] IR (KBr): 1590, 1653, 3287 cm⁻¹.

[1472] NMR ¹H (DMSO-d6, δ): 0.87 (t, 3H); 1.06 (t, 3H); 1.73 (q, 2H);1.82 (q, 2H); 3.06 (d, 1H); 3.19 (t, 2H); 3.48 (d, 1H); 5.24 (s, 2H);5.31 (d, 1H); 5.54 (d, 1H); 6.02 (s, 1H); 7.38 (s, 1H); 7.72 (t, 1H);7.85 (t, 1H); 8.15 (d, 1H); 8.28 (d, 1H).

Example 104(5R)-5-ethyl-5-hydroxy-12-(2-trimethylsilylethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1473](5R)-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(obtained according to the procedure described in the PCT PatentApplication WO 97/00876) is treated with 3-trimethylsilylpropanal(obtained according to Sarkar, T. K., et al., Tetrahedron (1990),vol.46, p. 1885) according to a procedure similar to that of Stage 95ein order to produce the expected solid (m.p.>250° C.).

[1474] IR (KBr): 1655, 1753, 3420 cm⁻¹.

[1475] NMR ¹H (DMSO-d6, δ): 0.11 (s, 9H); 0.88 (t, 3H); 0.91 (m, 2H);1.89 (q, 2H); 3.07 (d, 1H); 3.12 (m, 2H); 3.47 (d, 1H); 5.25 (s, 2H);5.33 (d, 1H); 5.41 (d, 1H); 5.54 (d, 1H); 6.02 (s, 1H); 7.39 (s, 1H);7.73 (t, 1H); 7.82 (t, 1H); 8.15 (s, 1H).

Example 105(5R)-12-butyl-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1476] The product of Example 84 is treated with valeraldehyde accordingto a procedure similar to Stage 95e to produce the expected solid (m.p.235-236° C.).

[1477] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 0.95 (t, 3H); 1.48 (m, 2H);1.67 (m, 2H); 1.85 (q, 2H); 3.06 (d, 1H); 3.20 (t, 2H); 3.46 (d, 1H);5.27 (s, 2H); 5.40 (d, 1H); 5.53 (d, 1H); 6.02 (s, 1H); 7.38 (s, 1H);7.64 (t, 1H); 7.87 (d, 1H); 8.36 (dd, 1H).

Example 106(5R)-5,12-diethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1478] The product of Example 84 is treated with propionaldehydeaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

[1479] NMR ¹H (DMSO-d6, δ): 0.86 (t, 3H); 1.31 (t, 3H); 1.85 (q, 2H);3.06 (d, 1H); 3.22 (q, 2H); 3.47 (d, 1H); 5.24 (s, 2H); 5.39 (d, 1H);5.53 (d, 1H); 6.03 (s, 1H); 7.38 (s, 1H); 7.64 (t, 1H); 7.87 (d, 1H);8.37 (dd, 1H).

Example 107(5R)-5-ethyl-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1480] 2-aminobenzonitrile is treated with isopentylmagnesium bromideaccording to a procedure similar to Stage 86a and the resultingamino-ketone is treated according to a procedure similar to Stage 86b.Stages 83f to 83h of the operating method of Example 83 above areapplied to the quinolone obtained. A solid is obtained (m.p. 263° C.).

[1481] IR (KBr): 1655, 1743, 3343 cm⁻¹.

[1482] NMR ¹H (DMSO-d6, δ): 0.85 (t, 3H); 1.00 (d, 6H); 1.54 (m, 2H);1.79 (m, 1H); 1.82 (m, 2H); 3.06 (4, 1H); 3.14 (m, 2H); 3.45 (d, 1H);5.20 (s, 2H); 5.38 (d, 1H); 5.52 (d, 1H); 5.99 (s, 1H); 7.37 (s, 1H);7.70 (t, 1H); 7.82 (t, 1H); 8.12 (d, 1H); 8.19 (d, 1H).

Example 108(5R)-5-ethyl-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1483] 2-aminobenzonitrile is treated by 4-fluorophenylmagnesium bromideaccording to a procedure similar to Stage 86a and the resultingamino-ketone is treated according to a procedure similar to Stage 86b.Stages 83f to 83h of the operating method of Example 83 above areapplied to the quinolone obtained.

Example 109(5R)-12-(2,6-difluorophenyl)-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1484] 2-aminobenzonitrile is treated by 2,6-difluorophenylmagnesiumbromide according to a procedure similar to Stage 86a and the resultingamino-ketone is treated according to a procedure similar to Stage 86b.Stages 83f to 83h of the operating method of Example 83 above areapplied to the quinolone obtained.

Example 110(5R)-12-(3,5-difluorophenyl)-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1485] 2-aminobenzonitrile is treated with 3,5-difluorophenylmagnesiumbromide according to a procedure similar to Stage 86a and the resultingamino-ketone is treated according to a procedure similar to Stage 86b.Stages 83f to 83h of the operating method of Example 83 above areapplied to the quinolone obtained.

Example 110 (5R)-5-ethyl-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1486] 2-aminobenzonitrile is treated with3,4,5-trifluorophenylmagnesium bromide according to a procedure similarto Stage 86a and the resulting amino-ketone is treated according to aprocedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained.

Example 112(5R)-5-ethyl-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1487] 2-aminobenzonitrile is treated with2,4,6-trifluorophenylmagnesium bromide according to a procedure similarto Stage 86a and the resulting amino-ketone is treated according to aprocedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained.

Example 113(5R)-5-ethyl-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1488] 2-aminobenzonitrile is treated with2,3,5,6-tetrafluorophenylmagnesium bromide according to a proceduresimilar to Stage 86a and the resulting amino-ketone is treated accordingto a procedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained.

Example 114(5R)-5-ethyl-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1489] 2-aminobenzonitrile is treated with2,3,4,5,6-pentafluorophenylmagnesium bromide according to a proceduresimilar to Stage 86a and the resulting amino-ketone is treated accordingto a procedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained.

Example 115(5R)-5-ethyl-9-fluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1490] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 4-fluorophenylmagnesium bromide ofStage 93b, and the resulting amino-ketone is treated according to aprocedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained.

[1491] NMR ¹H (DMSO): 0.86 (t, 3H); 1.83 (q, 2H); 3.06 (d, 1H); 3.46 (d,1H); 5.06 (dd, 2H); 5.37 (d, 1H); 5.49 (d, 1H); 6.04 (s, 1H); 7.43 (s,1H); 7.52 (t, 2H); 7.60 (t, 1H); 7.73 (m, 2H); 7.83 (t, 1H); 7.97 (d, 1H).

Example 116(5R)-12-(2,6-difluorophenyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1492] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 2,6-difluorophenylmagnesium bromideof Stage 93b, and the resulting amino-ketone is treated according to aprocedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained.

Example 117(5R)-12-(3,5-difluorophenyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1493] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 3,5-difluorophenylmagnesium bromideof Stage 93b, and the resulting amino-ketone is treated according to aprocedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained.

[1494] NMR ¹H (DMSO): 0.86 (t, 3H); 1.84 (q, 2H); 3.06 (d, 1H); 3.47 (d,1H); 5.15 (dd, 2H); 5.37 (d, 1H); 5.50 (d, 1H); 6.04 (s, 1H); 7.43 (s,3H); 7.55 (t, 1H); 7.63 (t, 1H); 7.87 (t, 1H); 7.98 (d, 1H).

Example 118(5R)-5-ethyl-9-fluoro-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1495] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 3,4,5-trifluorophenylmagnesiumbromide of Stage 93b and the resulting amino-ketone is treated accordingto a procedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained.

Example 119(5R)-5-ethyl-9-fluoro-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1496] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 2,4,6-trifluorophenylmagnesiumbromide of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

Example 120(5R)-5-ethyl-9-fluoro-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1497] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 2,3,5,6-tetrafluorophenylmagnesiumbromide of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

Example 121(5R)-5-ethyl-9-fluoro-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1498] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 2,3,4,5,6-pentafluorophenylmagnesiumbromide of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

Example 122(5R)-5-ethyl-9,10-difluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1499] 2-amino-4,5-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using 4-fluorophenylmagnesiumbromide of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

Example 123(5R)-12-(2,6-difluorophenyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1500] 2-amino-4,5-difluorobenzoic acid is treated according to aprocedure similar to Stages 83a to 83c using 2,6-difluorophenylmagnesiumbromide of Stage 83b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

Example 124(5R)-12-(3,5-difluorophenyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1501] 2-amino-4,5-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using 3,5-difluorophenylmagnesiumbromide of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

Example 125(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1502] 2-amino-4,5-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using3,4,5-trifluorophenylmagnesium bromide of Stage 93b, and the resultingamino-ketone is treated according to a procedure similar to Stage 86b.Stages 83f to 83h of the operating method of Example 83 above is appliedto the quinolone obtained.

Example 126(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1503] 2-amino-4,5-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using2,4,6-trifluorophenylmagnesium bromide of Stage 93b, and the resultingamino-ketone is treated according to a procedure similar to Stage 86b.Stages 83f to 83h of the operating method of Example 83 above areapplied to the quinolone obtained.

Example 127(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1504] 2-amino-4,5-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using2,3,5,6-tetrafluorophenylmagnesium bromide of Stage 93b, and theresulting amino-ketone is treated according to a procedure similar toStage 86b. Stages 83f to 83h of the operating method of Example 83 aboveare applied to the quinolone obtained.

Example 128(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1505] 2-amino-4,5-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using2,3,4,5,6-pentafluorophenylmagnesium bromide of Stage 93b, and theresulting amino-ketone is treated according to a procedure similar toStage 86b. Stages 83f to 83h of the operating method of Example 83 aboveare applied to the quinolone obtained.

Example 129(5R)-5-ethyl-9,11-difluoro-12-(4-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1506] 2-amino-4,6-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using 4-fluorophenylmagnesiumbromide of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

Example 130(5R)-12-(2,6-difluorophenyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1507] 2-amino-4,6-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using 2,6-difluorophenylmagnesiumbromide of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

Example 131(5R)-12-(3,5-difluorophenyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1508] 2-amino-4,6-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using 3,5-difluorophenylmagnesiumbromide of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

Example 132 (5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(3,4,5-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1509] 2-amino-4,6-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using3,4,5-trifluorophenylmagnesium bromide of Stage 93b, and the resultingamino-ketone is treated according to a procedure similar to Stage 86b.Stages 83f to 83h of the operating method of Example 83 above areapplied to the quinolone obtained.

Example 133 (5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(2,4,6-trifluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1510] 2-amino-4,6-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using2,4,6-trifluorophenylmagnesium bromide of Stage 93b, and the resultingamino-ketone is treated according to a procedure similar to Stage 86b.Stages 83f to 83h of the operating method of Example 83 above areapplied to the quinolone obtained.

Example 134(5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(2,3,5,6-tetrafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1511] 2-amino-4,6-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using2,3,5,6-tetrafluorophenylmagnesium bromide of Stage 93b, and theresulting amino-ketone is treated according to a procedure similar toStage 86b. Stages 83f to 83h of the operating method of Example 83 aboveare applied to the quinolone obtained.

Example 135(5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(2,3,4,5,6-pentafluorophenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1512] 2-amino-4,6-difluorobenzoic acid is treated according to aprocedure similar to Stages 93a to 93c using2,3,4,5,6-pentafluorophenylmagnesium bromide of Stage 93b, and theresulting amino-ketone is treated according to a procedure similar toStage 86b. Stages 83f to 83h of the operating method of Example 83 aboveare applied to the quinolone obtained.

Example 136(5R)-5-ethyl-9-fluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1513] The product of Example 84 is treated with butyraldehyde accordingto a procedure similar to Stage 95e in order to produce the expectedsolid.

Example 137(5R)-5-ethyl-9-fluoro-5-hydroxy-12-(3,3,3-trifluoropropyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1514] The product of Example 84 is treated with4,4,4-trifluorobutyraldehyde according to a procedure similar to Stage95e in order to produce the expected solid.

Example 138(5R)-5-ethyl-9-fluoro-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1515] The product of Example 84 is treated with 4-methylpentanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 139(5R)-5-ethyl-9-fluoro-5-hydroxy-12-pentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1516] The product of Example 84 is treated with hexanal according to aprocedure similar to Stage 95e in order to produce the expected solid.

Example 140(5R)-5-ethyl-9-fluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1517] The product of Example 84 is treated with 3-phenylpropanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

[1518] NMR ¹H (DMSO): 0.86 (t, 3H); 1.84 (q, 2H); 3.02 (m, 2H); 3.07 (d,1H); 3.44 (d, 1H); 3.51 (m, 2H); 5.01 (dd, 2H); 5.38 (d, 1H); 5.51 (d,1H); 6.02 (s, 1H); 7.22 (m, 5H); 7.37 (s, 1H); 7.62 (m, 1H); 7.89 (dd,1H); 8.40 (m, 1H).

Example 141(5R)-12-decyl-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1519] The product of Example 84 is treated with undecanal according toa procedure similar to Stage 95e in order to produce the expected solid.

Example 142(5R)-12-(2-cyclohexylethyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1520] The product of Example 84 is treated with 3-cyclohexylpropanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 143(5R)-12-(3,3-dimethylbutyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1521] The product of Example 84 is treated with 4,4-dimethylpentanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 144(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1522] The product of Stage 95d is treated with butyraldehyde accordingto a procedure similar to Stage 95e in order to produce the expectedsolid.

Example 145(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(3,3,3-trifluoropropyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1523] The product of Stage 95d is treated with4,4,4-trifluorobutyraldehyde according to a procedure similar to Stage95e in order to produce the expected solid.

Example 146(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1524] The product of Stage 95d is treated with 4-methylpentanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 147(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-pentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1525] The product of Stage 95d is treated with hexanal according to aprocedure similar to Stage 95e in order to produce the expected solid.

Example 148(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1526] The product of Stage 95d is treated with 3-phenylpropanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 149(5R)-12-decyl-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1527] The product of Stage 95d is treated with undecanal according to aprocedure similar to Stage 95e in order to produce the expected solid.

Example 150(5R)-12-(2-cyclohexylethyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1528] The product of Stage 95d is treated with 3-cyclohexylpropanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 151(5R)-12-(3,3-dimethylbutyl)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1529] The product of Stage 95d is treated with 4,4-dimethylpentanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 152(5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1530] The product of Example 100 is treated with butyraldehydeaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 153(5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-(3,3,3-trifluoropropyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1531] The product of Example 100 is treated with4,4,4-trifluorobutyraldehyde according to a procedure similar to Stage95e in order to produce the expected solid.

Example 154(5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-isopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1532] The product of Example 100 is treated with 4-methylpentanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 155(5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-pentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1533] The product of Example 100 is treated with hexanal according to aprocedure similar to Stage 95e in order to produce the expected solid.

Example 156(5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-phenethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1534] The product of Example 100 is treated with 3-phenylpropanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 157(5R)-12-decyl-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1535] The product of Example 100 is treated with undecanal according toa procedure similar to Stage 95e in order to produce the expected solid.

Example 158(5R)-12-(2-cyclohexylethyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1536] The product of Example 100 is treated with 3-cyclohexylpropanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 159(5R)-12-(3,3-dimethylbutyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1537] The product of Example 100 is treated with 4,4-dimethylpentanalaccording to a procedure similar to Stage 95e in order to produce theexpected solid.

Example 160(5R)-12-chloro-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1538] Ethyl 2,4-dichloro-3-quinoleinecarboxylate (obtained according toJ Heterocyclic Chem., 35, 627 (1998)) is treated according to aprocedure similar to Stages 83g to 83h of the operating method ofExemple 83 above.

[1539] NMR ¹H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.46 (d,1H); 5.27 (s, 2H); 5.40 (d, 1H); 5.52 (d, 1H); 6.03 (s, 1H); 7.41 (s,1H); 7.86 (t, 1H); 7.97 (t, 1H); 8.22 (d, 1H); 8.30 (d, 1H).

Example 161(5R)-5-ethyl-5-hydroxy-12-hydroxymethyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1540](5R)-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2b]quinoleine-3,15-dione(obtained according to the procedure described in the patent applicationWO 97/00876) is treated with methanol according to a procedure similarto Stage 95e in order to produce the expected compound.

[1541] NMR ¹H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 3.08 (d, 1H); 3.44 (d,1H); 5.19 (d, 2H); 5.38 (m, 3H); 5.52 (d, 1H); 5.80 (m, 1H); 5.98 (s,1H); 7.38 (s, 1H); 8.15 (m, 1H); 8.23 (m, 1H).

Example 162(5R)-5-ethyl-9-fluoro-5-hydroxy-12-isobutyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1542] The product of Example 84 is treated with 3-methylbutanalaccording to a procedure similar to Stage 95e in order to produce theexpected compound.

[1543] NMR ¹H (DMSO): 0.86 (t, 3H); 0.98 (d, 6H); 1.84 (q, 2H); 2.11 (m,1H); 3.05 (d, 1H); 3.12 (m, 2H); 3.46 (d, 1H); 5.25 (dd, 2H); 5.39 (d,1H); 5.52 (d, 1H); 1H); 7.39 (s, 1H); 7.65 (m, 1H); 7.87 (dd, 1H); 8.37(m, 1H).

Example 163(5R)-5-ethyl-9-fluoro-5-hydroxy-12-neopentyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1544] The product of Example 84 is treated with 3,3-dimethylbutanalaccording to a procedure similar to Stage 95e in order to produce theexpected compound.

[1545] NMR ¹H (DMSO): 0.86 (t, 3H); 1.01 (s, 9H); 1.84 (q, 2H); 3.05 (d,1H); 3.22 (m, 2H); 3.46 (d, 1H); 5.26 (dd, 2H); 5.38 (d, 1H); 5.52 (d,1H); 6.01 (s, 1H); 7.39 (s, 1H); 7.60 (m, 1H); 7.85 (dd, 1H); 8.46 (m,1H).

Example 164(5R)-5-ethyl-9-fluoro-12-(3-fluorophenyl)-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1546] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 3-fluorophenylmagnesium bromide ofStage 93b, and the resulting amino-ketone is treated according to aprocedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained.

[1547] NMR ¹H (DMSO): 0.86 (t, 3H); 1.84 (q, 2H); 3.06 (d, 1H); 3.46 (d,1H); 5.08 (m, 2H); 5.37 (d, 1H); 5.49 (d, 1H); 6.04 (s, 1H); 7.43 (s,1H); 7.48 (m, 2H); 7.61 (m, 2H); 7.73(m, 1H); 7.83(m, 1H); 7.97(m, 1H).

Example 165 (5R)-5-ethyl-9-fluoro-5-hydroxy-12-(4-trifluoromethylphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1548] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 4-trifluoromethylphenylmagnesiumbromide of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

[1549] NMR ¹H (DMSO): 0.86 (t, 3H); 1.83 (q, 2H); 3.06 (d, 1H); 3.46 (d,1H); 5.06 (dd, 2H); 5.37 (d, 1H); 5.49 (d, 1H); 6.04 (s, 1H); 7.43 (s,1H); 7.52 (t, 2H); 7.60 (t, 1H); 7.73 (m, 2H); 7.83 (t, 1H); 7.97 (d,1H).

Example 166 (5R)-5-ethyl-9-fluoro-5-hydroxy-12-(4-trifluoromethoxyphenyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1550] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 4-trifluoromethoxyphenylmagnesiumbromide of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

[1551] NMR ¹H (DMSO): 0.86 (t, 3H); 1.83 (q, 2H); 3.06 (d, 1H); 3.46 (d,1H); 5.06 (dd, 2H); 5.37 (d, 1H); 5.49 (d, 1H); 6.03 (s, 1H); 7.43 (s,1H); 7.59 (m, 1H); 7.68 (m, 2H); 7.81 (m, 1H); 7.97 (dd, 1H).

Example 167(5R)-12-(4-dimethylaminophenyl)-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1552] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93 a to 93c using 4-dimethylaminophenylmagnesiumchloride of Stage 93b, and the resulting amino-ketone is treatedaccording to a procedure similar to Stage 86b. Stages 83f to 83h of theoperating method of Example 83 above are applied to the quinoloneobtained.

[1553] NMR ¹H (DMSO): 0.86(t, 3H); 1.84 (q, 2H); 3.04 (s, 6H); 3.06 (d,1H); 3.46 (d, 1H); 5.10 (dd, 2H); 5.36 (d, 1H); 5.49 (d, 1H); 6.02 (s,1H); 6.95 (d, 2H); 7.40 (s, 1H); 7.49 (d, 2H); 7.57 (t, 1H); 7.90 (d,1H); 8.01 (t, 1H).

Example 168(5R)-12-[4-(tert-butyl)phenyl]-5-ethyl-9-fluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1554] 2-amino-4-fluorobenzoic acid is treated according to a proceduresimilar to Stages 93a to 93c using 4-tert-butylphenylmagnesium bromideof Stage 93b, and the resulting amino-ketone is treated according to aprocedure similar to Stage 86b. Stages 83f to 83h of the operatingmethod of Example 83 above are applied to the quinolone obtained.

[1555] NMR ¹H (DMSO): 0.86 (t, 3H); 1.40 (s, 9H); 1.85 (q, 2H); 3.05 (d,1H); 3.47 (d, 1H); 5.08 (dd, 2H); 5.37 (d, 1H); 5.49 (d, 1H); 6.04 (s,1H); 7.44 (s, 1H); 7.60 (m, 3H); 7.69 (d, 2H); 7.89 (m, 1H); 7.96 (m,1H).

Example 169(5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1556] The product of Example 100 is treated with butyraldehydeaccording to a procedure similar to Stage 95e in order to produce theexpected compound.

[1557] NMR ¹H (DMSO): 0.86 (t, 3H); 1.04 (t, 3H); 1.70 (q, 2H); 1.84 (q,2H); 3.05 (d, 1H); 3.14 (m, 2H); 3.47 (d, 1H); 5.25 (dd, 2H); 5.35 (d,1H); 5.52 (d, 1H); 6.07 (s, 1H); 7.38 (s, 1H); 7.67 (m, 1H); 7.78 (m,1H).

Example 170(5R)-12-(2-ethoxyethyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1558] The product of Example 100 is treated with 3-ethoxypropanalaccording to a procedure similar to Stage 95e in order to produce theexpected compound.

[1559] NMR ¹H (DMSO): 0.86 (t, 3H); 1.05 (t, 3H); 1.84 (q, 2H); 3.07 (d,1H); 3.43 (m, 5H); 3.77 (t, 2H); 5.26 (dd, 2H); 5.39 (d, 1H); 5.52 (d,1H); 6.03 (s, 1H); 7.39 (s, 1H); 7.67 (m, 1H); 7.79 (dd, 1H).

Example 171(5R)-5-ethyl-9,10,11-trifluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1560] Stages 95a to 95c are applied to 3,4,5-trifluoroaniline and theresulting quinolylmethanol is treated with (+)-EHHOPD according to aprocedure of Stage 83h in order to produce the expected compound.

[1561] NMR ¹H (DMSO): 0.87 (t, 3H); 1.83 (q, 2H); 3.07 (d, 1H); 3.45 (d,1H); 5.26 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.03 (s, 1H); 7.40 (s,1H); 8.09 (m, 1H); 8.86 (s, 1H).

Example 172(5R)-5-ethyl-9-fluoro-5-hydroxy-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolein-10-yltrifluorometanesulfonate

[1562] (5R)-5-ethyl-9-fluoro-5,10-dihydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino-[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione(28 mg, obtained according to the preparation 20 described in the patentapplication WO 98/28304) in anhydrous DMF solution (5 ml) is traited at0° C. with 1.1 equivalent of sodium hydride, then with 1.1 equivalent ofN-phenyltrifluorosulfonimide. The reaction medium is maintained underagitation for 2 h at ambient temperature, then poured into iced waterand extracted with ethyl. The organic phase is dried and concentratedthen the residue is taken up in ether and recovered by filtration toproduce the expected compound.

[1563] NMR ¹H (DMSO): 0.87 (t, 3H); 1.86 (q, 2H); 3.07 (d, 1H); 3.46 (d,1H); 5.29 (s, 1H); 5.40 (d, 1H); 5.52 (d, 1H); 6.04 (s, 1H); 7.43 (s,1H); 8.31 (d, 1H); 8.66 (d, 1H); 8.82 (s, 1H).

[1564] The following examples as defined below may be prepared accordingto preparation procedures as described above:

Example 174 5-ethyl-5-hydroxy-10-methyl-4,5,13,15-t6trahydro-1H,3H-oxépino[3′,4′:6,7]indolizino[1,2-b]quinoleine-3,15-dione

[1565] pf>250° C.; IR (KBr): 1614, 1658, 1724 cm⁻¹.

[1566] RMN-¹H (DMSO): 0,87(t, 3H); 1,86(q, 2H); 2,55 (s, 1H); 3,27 (dd,2H); 5,24 (s, 2H); 5,45 (dd, 2H); 7,38 (s, 1H); 7,69 (d, 1H); 7,88 (s,1H); 8,05 (s, 1H); 8.56 (s, 1H).

Example 175 chloride of9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(HCl salt of example 31) Example 176(5S)-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dioneExample 177 chloride of5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione (HCl salt ofexample 59) Example 178 chloride of9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(HCl salt of example 65) Example 179 chloride of9-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione (HCl salt of example64) Example 180 chloride of5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione(HCl salt of example 67) Example 181 chloride of12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione (HCl salt of example66) Example 182 chloride of5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione (HCl salt ofexample 39) Example 183(5S)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dioneExample 184 (5S)-12-butyl-5-ethyl-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione Example 1855-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione (base of example 44) Example 186(5S)-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione Example 187(5S)-5-ethyl-5-hydroxy-12-phenyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione

[1567] Pharmacological Study of the Products According to the Invention

[1568] 1. Relaxation Activity Test of DNA Induced by Topoisomerase 1

[1569] All the reactions are carried out in a 20 μl reaction bufferconstituted by 50 mM of Tris-HCl (pH 7.5), 50 mM of KCl, 0.5 mM ofdithiothreitol, 10 mM of MgCl₂, 0.1 mM of ethyldiamine tetraacetic acid(EDTA), 30 μg/ml of bovine serum albumin and 300 ng of supercoiled pUC19(Pharmacia Biotech, Orsay, France) with or without the compounds to betested at defined concentrations. All the compounds to be tested areinitially dissolved in dimethylsulphoxide (DMSO) at 50 mM, the otherdilutions being carried out with distilled water. The finalconcentration of DMSO does not exceed 1% (v/v). The reaction isinitiated by the addition of a unit of DNA topoisomerase 1 of purifiedcalf thymus (Gibco-BRL, Paisley, United Kingdom) and is carried out for15 minutes at 37° C. The reactions are stopped by the addition of 3 μlof a mixture containing 1% dodecyl sodium sulphate at 1%, 20 mM of EDTAand 500 μg/ml of K proteinase (Boehringer Mannheim, Meylan, France).After an additional incubation period of 30 minutes at 37° C., 2 μl of aloading buffer containing 10 mM of Na₂HPO₄, 0.3% of bromophenol blue et16% Ficoll are added to samples which are subjected to electrophoresisin agarose gels at 1.2% at 1 V/cm for 20 hours in a buffer containing 36mM of Tris-HCl at pH 7.8, 30 mM of Na₂HPO₄, 1 mM of EDTA and 2 μg/ml ofchloroquine. The gels are stained with 2 μg/ml of ethidium bromide,photographed under UV light at 312 nm with a camera and the fluorescentintensity is measured with a bioProfil camera (Vilber Lournat, Lyon,France) with a view to determining the percentage of relaxed DNA. Eachexperiment is carried out at least three times in duplicate.

[1570] In each experiment, the supercoiled plasmid DNA is incubatedalone or with topoisomerase 1. The reaction is completed within 15minutes. For each compound to be tested or control, the supercoiledplasmid DNA is incubated in the presence of 500 μM of compound to betested with enzyme or without enzyme plus the compound to be tested, atconcentrations of 10 μM, 100 μM, 200 μM and 500 μM. As indicated inTable I, Examples 2 to 4, 9 to 11 and 76 to 79 inhibit the relaxationactivity encouraged by topoisomerase 1 in a dose-dependent manner. TABLEI PERCENTAGE OF RELAXED DNA CONCENTRATION (μM) EXAMPLE 10 100 200 500Example 2 97.9 78.3 73.2 51.1 Example 3 79.9 59.9 55.0 45.7 Example 499.1 82.2 67.6 32.9 Example 9 77.1 33.9 29.7 20.4 Example 10 96.9 45.426.2 8.7 Example 11 65.0 50.3 39.8 31.0 Example 76 79.7 33.5 23.2 —Example 77 86.2 35.1 32.1 — Example 78 56.2 28.0 24.2 — Example 79 55.638.9 30.0 —

[1571] 2. Test on Cell Proliferation

[1572] a. Eight tumoral cell lines are used in this study: L1210 (mouselymphocytic leukemia), HCT15 and LOVO (cell lines of human colonadenocarcinoma), A549 (human lung carcinoma), A172, U373 et U87 (humanglioblastoma). All these lines are obtained from the American TypeCulture Collection (ATCC), Rockville, Md. The L1210 cell cultures insuspension are cultured in Dulbecco's modified Eagle's medium (DMEM)(BioWhitaker, Verviers, Belgium) together with 10% of foetal calf seruminactivated by heating, 2 mM of glutamine, 50 μg/ml of penicillin and 50μg/ml of streptomycin. The HT29 cells are cultured in mono-layercultures in a McCoy 5a medium (Gibco, Paisley, United Kingdom) togetherwith 10% of foetal calf serum inactivated by heat plus 2 mM of glutamineand 50 μg/ml of gentamycin. The other cells are cultured in an Earle'smodified essential medium (EMEM; Gibco, Paisley, United Kingdom)together with 5% foetal calf serum inactivated by heat, 2 mM ofglutamine, 50 U/ml of penicillin and 50 μg/ml of streptomycin. All thecell lines are cultured at 37° C. in a humidified atmosphere containing95% air and 5% CO₂.

[1573] Inhibition of the tumor cell line proliferation is determinedusing an MTT test. 1500 L1210 cells in a culture medium (according tothe needs of the cell medium) are seeded in a well of a micro-well plate(tissue culture level: 96 wells, flat bottom) 24 hours before treatmentwith the compounds to be tested. For these dose-response studies, thecells are incubated with each of the compounds to be tested or theircorresponding solvent (controls) for 48 hours over a final concentrationrange of 1.10⁻¹⁰ to 1.10⁻⁴ M. All the compounds are dissolved justbefore use in dimethylsulphoxide (DMSO) at a concentration of 50 mM.Other dilutions of the medicaments are carried out in the culturemedium. The final concentration of DMSO never exceeds 0.2% (v/v). Ascontrols, the solutions of medicaments are replaced with the solventwhich is diluted successively in the same way as the compounds to betested.

[1574] After the incubation period, the labeling reagent MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; Thiazolblue, Sigma M 565, Sigma, St Louis, Mo.) is added at a finalconcentration of 0.3 mg/ml to each well. The cells are incubated for 4hours at 37° C. in a humidified atmosphere. This stage allows themitochondrial dehydrogenase of the living cells to convert the yellowtetrazolium salt MTT into crimson formazan crystals. The supernatantpart is eliminated and the formazan crystals formed are solubilized withDMSO. The resultant coloured solution is quantified by absorbance at 570nm by using a multi-cuvette scanning spectrophotometer. The dataconcerning the proliferation is expressed as a percentage of livingcells in the treated wells, divided by the living cells in the controls.Each point represents the average of three independent experiments, eachexperiment represents six determinations.

[1575] For the other cell lines (HCT15, LOVO, A549, A172, U373, U87),1000 to 2000 cells are seeded in the well of a micro-well plate 24 hoursbefore medicinal treatment. They are incubated with each of thecompounds to be tested or their corresponding solvent (controls) for 72hours over a final concentration range of 1.10⁻¹⁰ to 1.10⁻⁶ M.

[1576] The results are expressed as percentages of the calculatedproliferation by the optical density (OD) of the cells treated with amedicament divided by the OD of the control cells (cells treated withDMSO). As represented in Table II, the compounds to be tested haveinhibited the proliferation of cells in a dose-dependent manner. TABLEII PERCENTAGE OF CELL PROLIFERATION Cell CONCENTRATION (nM) EXAMPLE line0.1 1 10 100 1 000 10 000 100 000 Example 3 L1210 87.22 68.92 42.6426.85 10.83 2.11 2.20 HCT15 86.00 84.00 58.00 44.00 18.00 9.00 13.00LOVO 108.00 86.00 54.00 31.00 23.00 10.00 12.00 A549 132.00 111.00 75.0039.00 35.00 10.00 11.00 A172 89.00 101.00 68.00 37.00 27.00 10.00 7.00U373 99.00 98.00 40.00 24.00 17.00 13.00 9.00 U87 108.00 85.00 42.0023.00 15.00 5.00 6.00 Example 4 L1210 92.14 97.14 91.08 86.28 46.7927.80 8.09 HCT15 91.00 92.00 86.00 78.00 54.00 20.00 7.00 LOVO 80.0075.00 79.00 69.00 38.00 21.00 5.00 A549 71.00 76.00 71.00 56.00 36.0022.00 12.00 A172 93.00 92.00 98.00 97.00 44.00 31.00 10.00 U373 86.0085.00 89.00 63.00 30.00 16.00 2.00 U87 98.00 101.00 98.00 74.00 11.006.00 2.00 Example 9 L1210 74.04 62.05 44.72 34.01 20.20 4.34 1.58 HCT1594.00 89.00 59.00 35.00 15.00 8.00 3.00 LOVO 74.00 85.00 44.00 31.0021.00 4.00 2.00 A549 91.00 88.00 50.00 31.00 23.00 5.00 3.00 A172 97.0089.00 44.00 36.00 19.00 3.00 1.00 U373 89.00 69.00 24.00 18.00 8.00 3.001.00 U87 105.00 72.00 14.00 7.00 4.00 2.00 6.00 Example 10 L1210 91.5197.94 89.28 67.32 31.51 19.78 3.65 HCT15 111.00 87.00 103.00 63.00 42.0017.00 9.00 LOVO 71.00 76.00 77.00 52.00 29.00 18.00 4.00 A549 71.0076.00 71.00 56.00 36.00 22.00 7.00 A172 93.00 92.00 91.00 60.00 39.0015.00 3.00 U373 96.00 104.00 87.00 35.00 20.00 10.00 2.00 U87 96.0079.00 89.00 17.00 6.00 5.00 2.00 Example 11 L1210 91.99 81.37 23.1616.83 5.59 1.45 1.04 HCT15 71.00 63.00 45.00 23.00 12.00 9.00 9.00 LOVO66.00 42.00 29.00 21.00 8.00 3.00 3.00 A549 82.00 44.00 29.00 26.00 4.003.00 2.00 A172 95.00 53.00 47.00 39.00 12.00 3.00 2.00 U373 50.00 30.0025.00 8.00 2.00 1.00 2.00 U87 40.00 21.00 12.00 6.00 1.00 1.00 1.00

[1577] b. Nine tumoral cell lines are used in this study: PC3, DU145(human prostate cell lines), MCF7 and MCF7-ADR (mammary cell lines, thesymbol “ADR” is used to indicate that the line has been renderedadriamycin-resistant), A427 (human lung adenocarcinoma), HT29 (humancolon adenocarcinoma cell line), T24s, T24r (human bladder cell line,the T24r's are resistant to adriamycin, amongst others). The PC3, DU145and A427 lines were obtained from the American Type Culture Collection(ATCC, Rockville, Md.). The MCF7 and MCF7-ADR cells were graciouslydonated by Dr Jacques Soudon (Pharmacell, Paris, France). The T24s andT24r cells were graciously donated by Dr Robert Kiss (Free University ofBrussels, Belgium). The HT29 cells were cultivated in single-layercultures in a 4.5 g/l DMEM medium (Gibco, Paisley, United Kingdom)completed with 10% heat-inactivated foetal calf serum plus 2mM glutamineand 50 g/ml gentamycin (Gibco, Paisley, United Kingdom). The other cellsare cultivated in a Earle's modified essential medium DMEM at 4.5 g/l(Gibco, Paisley, United Kingdom) completed with 10% heat-inactivatedfoetal calf serum, 2 mM glutamin (Gibco, Paisley, United Kingdom), 50U/ml penicillin and 50 g/ml streptomycin (BioWhitaker, Verviers,Belgium). All the cell lines are cultivated at 37° C. in a humidifiedatmosphere containing 95% air and 5% CO₂.

[1578] Ihibition of the tumour cell line proliferation is determinedusing a WST1 colorimetry test. 500 to 4000 cells in a culture medium(according to the needs of the cell medium) are seeded in a well of amicro-well plate (96 wells, flat bottom) 24 hours before treatment withthe compounds to be tested. For these concentration-response studies,the cells are incubated with each of the compounds to be tested or theircorresponding solvent (controls) for 72 hours over a final concentrationrange of 1×10−13 to 1×10−5 M. All the compounds are dissolved indimethylsulphoxide (DMSO) or in water for the water-soluble compounds.The following dilutions of the compounds of the present invention arecarried out in the culture medium such that the final concentration ofDMSO, when it is part of the vehicle's composition, is always 0.1%(v/v). As controls, the solutions of the compounds are replaced with thesolvent which is diluted successively in the same way as the compoundsto be tested.

[1579] After incubation, the labelling reagent WST1(4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2h-5-tetrazolio-1,3-benzene)(Boehringer Mannheim, Germany) is added at a final concentration of 9%to each well. The cells are incubated for 2 to 4 hours at 37° C. in ahumidified atmosphere. This stage allows the mitochondrial dehydrogenaseof the living cells to convert the orange tetrazolium salt WST1 intocrimson formazan crystals. The resultant coloured solution is quantifiedby a dual beam reading (450 and 690 nm) using a multi-cuvette scanningspectrophotometer.

[1580] The results are expressed in the form of a concentration table,expressed in mol/litre, including the 50% inhibitory concentration(IC₅₀). They are shown in Tables III A) and III B). Examples where thenumber is followed by an “s” correspond to the compound salts. Cpt, Adrand Tpt are the abbreviations respectively for camptothecin, adriamycinand topotecan. TABLE III A) Ex- am- ples PC3 DU145 A427 HT29 Cpt 10-7 to10-8 10-7 to 10-8 10-8 to 10-7 10-7 to 10-8 Adr 10-7 to 108  Tpt 10-6 to107  10-7 to 10-8 10-7 to 10-8 10-7 to 10-8  3 10-7 to 10-8 10-8 to 10-910-9 to 10-8 10-7 to 10-8 16 <10-13  10-10 to 10-9  10-13 to 10-12 10-8to 10-9 17 10-8 to 10-9 10-12 to 10-11 10-11 to 10-10 10-8 to 10-9 1810-13 to 10-12  10-9 to 10-10 10-11 to 10-10 10-8 to 10-9 19 10-8 to10-9  10-9 to 10-10 10-10 to 10-9  10-8 to 10-9 20 <10-13  10-10 to10-11 10-13 to 10-11 10-8 to 10-9 21 10-8 to 10-9 10-8 to 10-9 10-11 to10-10 10-7 to 10-8 22 10-7 to 10-8 10-8 to 10-9 10-9 to 10-8 10-7 to10-8 23 <10-13  10-10 to 10-11 10-12 to 10-13 10-8 to 10-9 24 10-10 to10-11 10-8 to 10-9 10-9 to 10-8 10-7 to 10-8 25 10-9 to 10-8  10-9 to10-10 10-10 to 10-9  10-8 to 10-9 26 10-8 to 10-9  10-9 to 10-10 10-10to 10-9  10-10 to 10-11 28 10-8 to 10-9 10-10 to 10-11 10-10 to 10-9 10-8 to 10-7 29 10-13 to 10-12  10-9 to 10-10 10-11 to 10-10 10-8 to10-9 34  10-9 to 10-10 10-8 to 10-9 10-9 to 10-8 10-7 to 10-8 37 10-7 to10-8 10-8 to 10-9 10-9 to 10-8 10-7 to 10-8 38 10-7 to 10-8 10-8 to 10-910-9 to 10-8 10-7 to 10-8 39 10-7 to 10-8 10-7 to 10-8 10-9 to 10-8 10-8to 10-9  39s 10-7 to 10-8 10-8 to 10-9 10-9 to 10-8 10-7 to 10-8 42 10-7to 10-8 10-8 to 10-9 10-9 to 10-8 10-8 to 10-9  44s 10-8 to 10-7 10-8 to10-7 10-7 to 10-8 49 10-7 to 10-8 10-8 to 10-9 10-11 to 10-10 10-8 to10-9 50 10-8 to 10-7 10-10 to 10-11 10-8 to 10-7 10-7 to 10-8 53 10-7 to10-8 10-8 to 10-9 10-9 to 10-8 10-7 to 10-8 54 10-7 to 10-8 10-8 to 10-910-8 to 10-7 10-7 to 10-8 57  10-9 to 10-10 10-9 to 10-8 10-7 to 10-8 57s 10-7 to 10-8 10-8 to 10-7 10-8 to 10-7 58 10-7 to 10-8  10-9 to10-10 10-8 to 10-9 10-7 to 10-8  58s 10-7 to 10-8  10-9 to 10-10 10-9 to10-8 10-8 to 10-9 59 10-7 to 10-8 10-8 to 10-9 10-8 to 10-7 10-7 to 10-8 59s 10-8 to 10-7 10-9 to 10-8 10-8 to 10-9 60 10-7 to 10-8  10-9 to10-10  10-9 to 10-10 10-8 to 10-9 63 10-7 to 10-8 10-8 to 10-9 10-9 to10-8 10-7 to 10-8  63s 10-8 to 10-7 10-8 to 10-7 10-8 to 10-7 64 10-7 to10-8 10-10 to 10-11 10-9 to 10-8 10-8 to 10-9 65 10-8 to 10-7 10-8 to10-7 10-7 to 10-8 67 10-8 to 10-9 10-9 to 10-8 10-7 to 10-8 81 10-8   10-9 82 3.10-8   7.10-9

[1581] TABLE III B) Examples MCF7 MCF7-ADR T24S T24R Cpt 10-6 to 10-710-8 to 10-9 Adr 10-5 to 10-6 >10-4 Tpt 10-5 to 10-6 10-5 to 10-6  310-6 to 10-7 10-7 to 10-8 12 10-6 to 10-7 10-7 to 10-8 16 10-7 to 10-810-8 to 10-9 17 10-7 to 10-8 10-13 to 10-12 18 10-7 to 10-8 10-8 to 10-919 10-7 to 10-8  10-9 to 10-10 22 10-6 to 10-7 10-8 to 10-9 23 10-7 to10-8  10-9 to 10-10 25 10-6 to 10-7 10-8 to 10-9 26 10-6 to 10-7 10-8 to10-9 28 10-7 to 10-8 10-8 to 10-9  39s 10-6 to 10-7 10-8 to 10-9 10-7 to10-8 42 10-6 to 10-7 10-8 to 10-9 43 <10-13 10-7 to 10-8 44 10-7 to 10-810-7 to 10-8  44s 10-8 to 10-9 10-8 to 10-9 45 10-8 to 10-9 10-7 to 10-8 45s 10-13 to 10-12 10-7 to 10-8  49s 10-8 to 10-9 10-7 to 10-8 57 10-6to 10-7  57s 10-10 to 10-9  10-8 to 10-9 59 10-6 to 10-7  59s 10-10 to10-9  10-8 to 10-9 61 10-7 to 10-8 10-6 to 10-7  63s  10-9 to 10-10 10-7to 10-8 65 10-8 to 10-9 10-7 to 10-8 67 10-6 to 10-7 71 10-6 to 10-710-7 to 10-8 10-7 to 10-8

[1582] c. Adenocarcinoma HT29 cells from the human colon are cultured ina single layer at 37° in a humidified atmosphere containing 95% of airand 5% of CO₂, in a modified essential Earle's medium at 4.5 g/l (Gibco,Paisley, United Kingdom); completed with 10% of inactivated foetal calfserum, 2 mM of glutamine, and 50 μg/ml of gentamycin (Gibco, Paisley,United Kingdom).

[1583] Approximately 2000 cells are seeded with the culture medium abovein the wells of a microplate (96 wells, flat-bottomed) and incubated for24 hours. Solutions in N,N-dimethyl-acetamide (DMA) of each of theexamples of the invention, diluted in the culture medium so that thefinal concentration of DMA is 0.1% (v/v), are added to the platecultures in order to obtain final concentration ranges from 1×10⁻¹³ to1×10⁻⁵ M, and the cells are incubated for 72 hours.

[1584] The WST1 staining reagent, (Boehringer Mannheim, Germany) is thenadded to each well at a final concentration of 9%, and the cells areincubated for 2 hours at 37° C. This stage allows the mitochondrialdeshydrogenase of the living cells to convert WST1 orange tetrazoliumsalt into crimson formazan. The resulting stained solutions arequantified by dual-beam detection (450 and 690 m) using a multi-cuvettescanning spectrophotometer.

[1585] The results shown in the following table III C) are expressed interms of inhibitory concentration at 50% (IC₅₀, in nM), accompanied by aconfidence interval. The inhibitory activities of the adenocarcinomaHT29 cell proliferation of the human colon obtained with the examples ofthe invention are assessed, these activities being, in an unexpectedfashion, superior to the activity of the reference compound(corresponding to a compound of formula I_(A) whereinR₁═R₂═R₃═R₄═R₅═R₆═H) described in the PCT Patent Application WO97/000876. TABLE III C) Biological activity IC₅₀ (nM) Confidenceinterval Reference 30 24-39 84 2.5 1.0-7.2 87 16 11-23 88 12  9-14 89 13 8-19 91 11  8-15 93 12  7-21 95 8.5  4-16 97 11  7-17 98 2.1 1.5-2.7 995.0 1.7-16  100 2.2 1.4-3.3 102 8 4.7-15  104 8.6  3-26 105 9.5  5-17106 3.5 2.3-5.4 115 0.26 0.04-0.65 117 0.25 140 3.2 1.8-5.3 160 5.54.2-7.1 162 12 8.5-17  163 6 164 2.7 1.5-4.8 165 1.7 0.6-5   166 8.95.2-15  167 13  7-23 169 2.3 1.6-3.4 170 0.85 0.38-7.1  171 8.2 5.1-13 

1. Compounds of general formula (A₁) or (A₂)

in racemic or enantiomeric form or any combinations of these forms, inwhich Z₁ represents a lower alkyl, a lower alkenyl, a lower alkynyl, alower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio loweralkyl; Z₂, Z₃, Z₄, Z₅ and Z₆ represent, independently, i) H, halo, lowerhaloalkyl, alkyl containing 1 to 12 carbon atoms optionnally substitutedby one or more halo radicals indentical or different, lower alkenyl,cycloalkyl, cycloalkyl lower alkyl, cyano, lower cyanoalkyl, nitro,lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lowerhydrazinoalkyl, azido, lower azidoalkyl, lower alkyl lowersulphonylalkyl, —(CH₂)_(m)NZ′₆Z′₇, —(CH₂)_(m)OZ′₆, —(CH₂)_(m)SZ′₆,—(CH₂)_(m)CO₂Z′₆, —(CH₂)_(m)NZ′₆C(O)Z₈, —(CH₂)_(m)C(O)Z₈,—(CH₂)_(m)OC(O)Z₈, —O(CH₂)_(m)NZ′₆Z′₇, —OC(O)NZ′₆Z′₇,—OC(O)(CH₂)_(m)CO₂Z′₆, —OSO₂Z₇, —(CH₂)_(m)N(CH₃)(CH₂)_(n)NZ′₆Z′₇,—(CH₂)_(m)OC(O)NZ′₆Z′₇, —(CH₂)_(m)S(O)_(q)Z₁₁, —(CH₂)_(m)P(O)Z₁₂Z₁₃,—(CH₂)₂P(S)Z₁₂Z₁₃, —(CH₂)_(m)SiZ′₁₁Z′₁₂Z′₁₃; or ii) —(CH₂)_(n)[N═X],—OC(O)[N═X], —(CH₂)_(m)OC(O)[N═X], aryl or lower arylalkyl, eachsubstituted (i.e. substituted between once and four times on the arylgroup or the heterocycle) or non substituted in which the substituent isa lower alkyl, lower arylalkyl, halo, hydroxy, —OCF₃, nitro, amino,lower alkylamino, di(lower alkyl)amino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl or iii) Z₃ and Z₄or Z₄ and Z₅ form together a chain with 3 or 4 members in which theelements of the chain are selected from the group constituted by CH,CH₂, O, S, N or NZ₉; Z₇ represents a lower alkyl radical optionnallysubstituted by one or more halo radicals identical or different, or anaryl optionnally susbtituted by one or more lower alkyl radicalsidentical or different; Z′₆ and Z′₇ represent, independently, i) H, alower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, loweraminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, loweralkoxy lower alkyl, lower haloalkyl, or ii) aryl or lower arylalkyl,each substituted (i.e. substituted between once and four times on thearyl group) or non substituted in which the substituent is a loweralkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl; Z₈ represents i)H, a lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, loweralkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl loweralkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, lowerhaloalkyl, or ii) aryl or lower arylalkyl, each substituted (i.e.substituted between once and four times on the aryl group) or nonsubstituted, in which the substituent is a lower alkyl, halo, nitro,amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, loweralkoxy or lower alkoxy lower alkyl; Z₉ represents i) H, a lower alkyl,lower haloalkyl, or ii) aryl or lower arylalkyl, each substituted or nonsubstitutued in which the substituent is lower alkyl, halo, nitro,amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, loweralkoxy or lower alkoxy lower alkyl; Z₁₀ represents i) H, a lower alkyl,lower haloalkyl, lower alkoxy, or ii) aryl substituted (i.e. having oneto four substituents on the aryl group)or non substituted in which thesubstitutent is lower alkyl, lower haloalkyl, lower hydroxyalkyl orlower alkoxy lower alkyl; Z₁₁ represents a lower alkyl, aryl,—(CH₂)_(m)OZ₁₄, —(CH₂)_(m)SZ₁₄, —(CH₂)₂NZ₁₄Z₁₅ or —(CH₂)_(m)[N═X]; Z₁₂and Z₁₃ represent, independently, a lower alkyl, aryl, lower alkoxy,aryloxy or amino; Z′₁₁, Z′₁₂ and Z′₁₃ represent, independently, H or alower alkyl radical; Z₁₄ and Z₁₅ represent, independently, H, loweralkyl or aryl; Z₁₆ represents H or —OZ₂₁; Z₁₇ represents —OZ′₆ or—NZ′₆Z′₇; Z₁₈ and Z₁₉ represent, independently, H, halo, lower alkyl,lower alkoxy or hydroxy; Z₂₀ represents H or halo; Z₂₁ represents H, alower alkyl, —CHO or —C(O)(CH₂)_(m)CH₃; Z_(p) represents H or an easilycleavable group preferably chosen from the groups corresponding to theformula —C(O)—A—NZ₂₂Z₂₃, in which A represents a linear or branchedalkylene radical optionally substituted by a radical chosen from thefree, esterified or salified hydroxy, halogen, free, esterified orsalified carboxy, amino, mono or dialkylamino radicals; Z₂₂ and Z₂₃represent, independently, H, a lower alkyl, lower hydroxyalkyl, loweralkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl loweralkyl, lower alkenyl, lower alkoxy lower alkyl, lower haloalkyl, orsubstituted or non substituted aryl or lower arylalkyl (i.e.,substituted one to four times on the aryl group), in which thesubstituent is a lower alkyl, halo, nitro, amino, lower alkylamino,lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy loweralkyl; m is an integer comprised between 0 and 6; n is 1 or 2; and qrepresents an integer from 0 to 2; and [N═X] represents a heterocyclicgroup with 4 to 7 members with the nitrogen atom which is a member ofthe heterocyclic ring, and X representing the chain necessary tocomplete said heterocyclic group and selected from the group constitutedby O, S, CH₂, CH, N, NZ₉ and C(O)Z₁₀; or pharmaceutically acceptablesalts of thereof.
 2. Compounds of general formula (A₁) or (A₂) asclaimed in claim 1, in racemic or enantiomeric form or any combinationsof these forms, characterized in that Z₁ represents a lower alkyl, alower alkenyl, a lower alkynyl, a lower haloalkyl, a lower alkoxy loweralkyl or lower alkylthio lower alkyl; Z₂ represents H, halo or —OSO₂Z₇;Z₃, Z₄ and Z₅ represent, independently, i) H, halo, lower haloalkyl,lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lowernitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl,azido, lower azidoalkyl, —(CH₂)_(m)NZ′₆Z′₇, —(CH₂)_(m)OZ′₆,—(CH₂)_(m)SZ′₆, —(CH₂)_(m)CO₂Z′₆, —(CH₂)_(m)NZ′₆C(O)Z₈,—(CH₂)_(m)C(O)Z₈, —(CH₂)_(m)OC(O)Z₈, —O(CH₂)_(m)NZ′₆Z′₇, —OC(O)NZ′₆Z′₇,—OC(O)(CH₂)_(m)CO₂Z′₆, —OSO₂Z₇ or ii) —(CH₂)_(n)[N═X], —OC(O)[N═X],—(CH₂)_(m)OC(O)[N═X] (in which [N═X], in this invention, represents aheterocyclic group with 4 to 7 members with the nitrogen atom N, whichis a member of the heterocyclic group, and X represents the remainingmembers, which are necessary to complete the heterocylic group, selectedfrom the group constituted by O, S, CH₂, CH, N, NZ₉ and COZ₁₀), aryl orlower arylalkyl, each substituted (i.e. substituted between once andfour times on the aryl group or the heterocycle) or non substituted inwhich the substituent is a lower alkyl, halo, nitro, amino, loweralkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or loweralkoxy lower alkyl or iii) Z₃ and Z₄ or Z₄ and Z₅ form together a chainwith 3 or 4 members in which the elements of the chain are selected fromthe group constituted by CH, CH₂, O, S, N or NZ₉; Z₆ represents i) H,halo, lower haloalkyl, alkyl containing 1 to 12 carbon atoms optionnallysubstituted by one or more halo radicals indentical or different, loweralkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl,cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower alkyl lowersulphonylalkyl, lower hydroxyalkyl, nitro, —(CH₂)_(m)C(O)Z₈,—(CH₂)_(m)NZ′₆C(O)Z₈, —(CH₂)_(m)NZ′₆Z′₇,—(CH₂)_(m)N(CH₃)(CH₂)_(n)NZ′₆Z′₇, —(CH₂)_(m)OC(O)Z₈,—(CH₂)_(m)OC(O)NZ′₆Z′₇, —(CH₂)_(m)S(O)_(q)Z₁₁, —(CH₂)_(m)P(O)Z₁₂Z₁₃,—(CH₂)₂P(S)Z₁₂Z₁₃, —(CH₂)_(m)SiZ′₁₁Z′₁₂Z′₁₃; or ii) —(CH₂)_(n)[N═X],—OC(O)[N═X], —(CH₂)_(m)OC(O)[N═X], each substituted (i.e. substitutedbetween once and four times on the heteroaryl group) or non substitutedin which the substituent is a lower alkyl, lower arylalkyl, halo,hydroxy, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl; or iii) aryl orlower arylalkyl, each substituted (i.e. substituted between once andfour times on the aryl group) or non substituted in which thesubstituent is a lower alkyl, halo, hydroxy, nitro, —OCF₃, amino, loweralkylamino, di(lower alkyl)amino, lower haloalkyl, lower hydroxyalkyl,lower alkoxy or lower alkoxy lower alkyl; Z₇ represents a lower alkylradical optionnally substituted by one or more halo radicals identicalor different, or an aryl optionnally susbtituted by one or more loweralkyl radicals identical or different; Z′₆ and Z′₇ represent,independently, i) H, a lower alkyl, lower hydroxyalkyl, lower alkyllower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl,lower alkenyl, lower alkoxy lower alkyl, lower haloalkyl, or ii) aryl orlower arylalkyl, each substituted (i.e. substituted between once andfour times on the aryl group) or non substituted in which thesubstituent is a lower alkyl, halo, nitro, amino, lower alkylamino,lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy loweralkyl; Z₈ represents i) H, a lower alkyl, lower hydroxyalkyl, amino,lower alkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl,cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, loweralkoxy lower alkyl, lower haloalkyl, or ii) aryl or lower arylalkyl,each substituted (i.e. substituted between once and four times on thearyl group) or non substituted, in which the substituent is a loweralkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl; Z₉ represents i)H, a lower alkyl, lower haloalkyl, or ii) aryl or lower arylalkyl, eachsubstituted or non substitutued in which the substituent is lower alkyl,halo, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl; Z₁₀ representsi) H, a lower alkyl, lower haloalkyl, lower alkoxy, or ii) arylsubstituted (i.e. having one to four substituents on the aryl group)ornon substituted in which the substitutent is lower alkyl, lowerhaloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl; Z₁₁represents a lower alkyl, aryl, —(CH₂)_(m)OZ₁₄, —(CH₂)_(m)SZ₁₄,—(CH₂)₂NZ₁₄Z₁₅ or —(CH₂)_(m)[N═X]; Z₁₂ and Z₁₃ represent, independently,a lower alkyl, aryl, lower alkoxy, aryloxy or amino; Z′₁₁, Z′₁₂ and Z′₁₃represent, independently, H or a lower alkyl radical; Z₁₄ and Z₁₅represent, independently, H, lower alkyl or aryl; Z₁₆ represents H or—OZ₂₁; Z₁₇ represents —OZ′₆ or —NZ′₆Z′₇; Z₁₈ and Z₁₉ represent,independently, H, halo, lower alkyl, lower alkoxy or hydroxy; Z₂₀represents H or halo; Z₂₁ represents H, a lower alkyl, —CHO or—C(O)(CH₂)_(m)CH₃; Z_(p) represents H or an easily cleavable grouppreferably chosen from the groups corresponding to the formula—C(O)—A—NZ₂₂Z₂₃, in which A represents a linear or branched alkyleneradical optionally substituted by a radical chosen from the free,esterified or salified hydroxy, halogen, free, esterified or salifiedcarboxy, amino, mono or dialkylamino radicals; Z₂₂ and Z₂₃ represent,independently, H, a lower alkyl, lower hydroxyalkyl, lower alkyl loweraminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, loweralkenyl, lower alkoxy lower alkyl, lower haloalkyl, or substituted ornon substituted aryl or lower arylalkyl (i.e., substituted one to fourtimes on the aryl group), in which the substituent is a lower alkyl,halo, nitro, amino, lower alkylamino, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl; m is an integercomprised between 0 and 6; n is 1 or 2; and q represents an integer from0 to 2; and [N═X] represents a heterocyclic group with 4 to 7 memberswith the nitrogen atom which is a member of the heterocyclic ring, and Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, S, CH₂, CH, N, NZ₉ and COZ₁₀;or pharmaceutically acceptable salts of thereof.
 3. Compounds as claimedin claim 1 or 2, characterized in that Z₂ represents H or halo orpharmaceutically acceptable salts of thereof.
 4. Compounds as claimed inclaim 1 or 2, characterized in that Z₃ represents halo; orpharmaceutically acceptable salts of thereof.
 5. Compounds as claimed inany of claims 1 to 4, characterized in that Z₁ represents a lower alkyl;Z₂ represents H or halo; Z₃, Z₄ and Z₅ represent, independently, i) H,halo, lower alkyl, —(CH₂)_(m)NZ′₆, Z′₇, —(CH₂)_(m)OZ′₆, —OSO₂Z₇ or ii)—(CH₂)_(n)[N═X] or iii) Z₃ and Z₄ or Z₄ and Z₅ form together a chainwith 3 or 4 members in which the elements of the chain are selected fromthe group constituted by CH, CH₂, O, S, N or NZ₉; Z₆ represents i) H,halo, alkyl containing 1 to 12 carbon atoms optionnally substituted byone or more halo radicals indentical or different, lower alkoxy loweralkyl, cycloalkyl, cycloalkyl lower alkyl, lower hydroxyalkyl,—(CH₂)_(m)NZ′₆Z′₇, —(CH₂)mSiZ′₁₁Z_(12′)Z′₁₃; or ii) —(CH₂)_(n)[N═X]substituted or non substituted in which the substituent is a lower alkylor lower arylalkyl or iii) aryl or lower arylalkyl, each substituted ornon substituted in which the substituent is a lower alkyl, halo, —OCF₃,di(lower alkyl)amino or lower haloalkyl; Z₇ represents a lower alkylradical optionnally substituted by one or more halo radicals identicalor different; Z′₆ and Z′₇ represent, independently, i) H, a lower alkyl,or ii) lower arylalkyl; Z₉ represents a lower alkyl or lower arylalkyl;Z′₁₁, Z′₁₂ and Z′₁₃ represent, independently, a lower alkyl radical; Z₁₆represents H or —OZ₂₁; Z₁₇ represents —OZ′₆ or —NZ′₆Z′₇; Z₁₈ and Z₁₉represent, independently, H, halo; Z₂₀ represents H; Z₂₁ represents H, alower alkyl or —C(O)(CH₂)_(m)CH₃; Z_(p) represents H or a groupcorresponding to the formula —C(O)—A—NZ₂₂Z₂₃, in which A represents alinear or branched alkylene radical optionally substituted by a radicalchosen from the free, esterified or salified hydroxy, halogen, free,esterified or salified carboxy, amino, mono or dialkylamino radicals;Z₂₂ and Z₂₃ represent, independently, H, a lower alkyl; m is an integercomprised between 0 and 6; n is 1 or 2; and q represents an integer from0 to 2; and [N═X] represents a heterocyclic group with 4 to 7 members, Xrepresenting the chain necessary to complete said heterocyclic group andselected from the group constituted by O, CH₂, CH, N and NZ₉; orpharmaceutically acceptable salts of thereof.
 6. Compounds as claimed inany of claims 1 to 5, characterized in that Z₁₈, Z₁₉ and Z₂₀ representH; or pharmaceutically acceptable salts of thereof.
 7. Compounds asclaimed in any of claims 1 to 6, characterized in that Z₁ representsethyl; or pharmaceutically acceptable salts of thereof.
 8. Compounds asclaimed in claim 1 or 2, characterized in that Z_(p) represents a groupcorresponding to the formula —C(O)—A—NZ₂₂Z₂₃; or pharmaceuticallyacceptable salts of thereof.
 9. Compounds as claimed in claim 1 or 2,characterized in that Z_(p) represents H; or pharmaceutically acceptablesalts of thereof.
 10. Compounds as claimed in claim 1 or 2,characterized in that they correspond to the formula (A1)

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₁₈, Z₁₉, Z₂₀ and Z_(p) are as definedin claim 1; or pharmaceutically acceptable salts of thereof. 11.Compounds as claimed in claim 1 or 2, characterized in that theycorrespond to the formula (A2)

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₁₆, Z₁₇, Z₁₈, Z₁₉, Z₂₀ and Z_(p) are asdefined in claim 1; or pharmaceutically acceptable salts of thereof. 12.Compounds as claimed in claim 1 or 2, characterized in that Z₆represents —(CH₂)_(m)SiZ′₁₁Z′₁₂Z′₁₃; or pharmaceutically acceptablesalts of thereof.
 13. Compounds as claimed in claim 12, characterized inthat they correspond to the following formula:(5R)-5-ethyl-9,10-difluoro-5-hydroxy-12-(2-trimethylsilylethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;(5R)-5-ethyl-5-hydroxy-12-(2-trimethylsilylethyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;14. Compounds as claimed in claim 1 or 2, characterized in that Z₂represents H or halo, Z₃ represents halo, Z₄ represents H, halo or loweralkyl, Z₅ represents H or halo, and Z₆ represents H, lower alkyl or—(CH₂)_(n)[N═X] substituted in which the substituent is a lower alkyl;or pharmaceutically acceptable salts of thereof.
 15. Compounds asclaimed in claim 14, characterized in that they correspond to thefollowing formula:(5R)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;(5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;or pharmaceutically acceptable salts of thereof.
 16. Compounds asclaimed in claim 1 or 2, characterized in that they correspond to theformula

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₁₈, Z₁₉, Z₂₀ and Z_(p) are as definedin claim 1; or pharmaceutically acceptable salts of thereof.
 17. Amethod of treating cancer in warm-blooded animals comprisingadministering to warm-blooded animals in need thereof a camptothecinanalog characterized in that said analog is a [A,B,C,D,E] pentacycliccompound, the cycles [A,B,C,D]

comprising any substitution on the various sites available forsubstitution(s), and the [E] cycle being a 7-ring member β-hydroxylactone ring of the formula

wherein R₁ is selected from the group consisting of alkyl of 1 to 6carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms, haloalkyl of 1to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms andalkylthioalkyl of 2 to 12 carbon atoms, R_(p) is hydrogen or an easilycleavable group, R₁₈ and R₁₉ are individually selected from the groupconsisting of hydrogen, halogen, OH and alkyl and alkoxy of 1 to 6carbon atoms and its non-toxic, pharmaceutically acceptable salts.
 18. Amethod of treating cancer according to claim 17, the cycles [A,B,C,D]comprising any substitution on the sites 8, 9, 10, 11, 12 or
 13. 19. Amethod of treating cancer according to claim 17, the cycles [A,B,C,D]comprising any substitution on the sites 8, 9, 10, 11 or
 12. 20. Amethod of treating cancer according to claim 17, the cycles [A,B,C,D]comprising any substitution on the sites 9, 10, 11 or
 12. 21. A methodof treating cancer in warm-blooded animals comprising administering towarm-blooded animals in need thereof a camptothecin having 5 rings witha 7-ring member β-hydroxy lactone ring of the formula

wherein R₁ is selected from the group consisting of alkyl of 1 to 6carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms, haloalkyl of 1to 6 carbon atoms, alkoxy alkyl of 2 to 12 carbon atoms andalkylthioalkyl of 2 to 12 carbon atoms, R_(p) is hydrogen or an easilycleavable group, R₁₈ and R₁₉ are individually selected from the groupconsisting of hydrogen, halogen, OH and alkyl and alkoxy of 1 to 6carbon atoms and its non-toxic, pharmaceutically acceptable salts.
 22. Amethod of treating cancer as claimed in claim 17 or 21, characterized inthat cancer is selected from the group consisting of leukemia, coloncancer, lung cancer, prostate cancer, breast cancer, melanoma, ovariancancer and gastric cancer.
 23. A method of treating cancer as claimed inclaim 22, characterized in that cancer is selected from the groupconsisting of leukemia, colon cancer, lung cancer, prostate cancer andbreast cancer.
 24. A method as claimed in any of claims 17 to 23characterized in that R₁₈ and R₁₉ are hydrogen.
 25. A method as claimedin any of claims 17 to 24 characterized in that R_(p) is hydrogen.
 26. Amethod as claimed in any of claims 17 to 25 characterized in that R₁ isethyl.
 27. A method as claimed in any of claims 17 to 26 characterizedin that camptothecin analog is selected from:(5R)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;(5R)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4:6,7]indolizino[1,2-b]quinolin-12-yl-methyl]-4-methyl-hexahydropyridiumchloride;(5R)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;(5R)-5-ethyl-9,11-difluoro-5-hydroxy-12-propyl-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione;or its pharmaceutically acceptable salts thereof.